Convergent evolution of SIV env after independent inoculation of rhesus macaques with infectious proviral DNA

International Nuclear Information System (INIS)

Buckley, Kathleen A.; Li Peilin; Khimani, Anis H.; Hofmann-Lehmann, Regina; Liska, Vladimir; Anderson, Daniel C.; McClure, Harold M.; Ruprecht, Ruth M.

2003-01-01

The env gene of three simian immunodeficiency virus (SIV) variants developed convergent mutations during disease progression in six rhesus macaques. The monkeys had been inoculated with supercoiled plasmids encoding infectious proviruses of SIVmac239 (a pathogenic, wild-type strain), SIVΔ3 (the live attenuated vaccine strain derived from SIVmac239), or SIVΔ3+ (a pathogenic progeny virus that had evolved from SIVΔ3). All six monkeys developed immunodeficiency and progressed to fatal disease. Although many divergent mutations arose in env among the different hosts, three regions consistently mutated in all monkeys studied; these similar mutations developed independently even though the animals had received only a single infectious molecular clone rather than standard viral inocula that contain viral quasispecies. Together, these data indicate that the env genes of SIVmac239, SIVΔ3, and SIVΔ3+, in the context of different proviral backbones, evolve similarly in different hosts during disease progression

Canine distemper outbreak in rhesus monkeys, China.

Science.gov (United States)

Qiu, Wei; Zheng, Ying; Zhang, Shoufeng; Fan, Quanshui; Liu, Hua; Zhang, Fuqiang; Wang, Wei; Liao, Guoyang; Hu, Rongliang

2011-08-01

Since 2006, canine distemper outbreaks have occurred in rhesus monkeys at a breeding farm in Guangxi, People's Republic of China. Approximately 10,000 animals were infected (25%-60% disease incidence); 5%-30% of infected animals died. The epidemic was controlled by vaccination. Amino acid sequence analysis of the virus indicated a unique strain.

Single subcutaneous dosing of cefovecin in rhesus monkeys (Macaca mulatta)

DEFF Research Database (Denmark)

Bakker, J.; Thuesen, Line Risager; Braskamp, G.

2011-01-01

was to determine whether cefovecin is a suitable antibiotic to prevent skin wound infection in rhesus monkeys. Therefore, the pharmacokinetics (PK) of cefovecin after a single subcutaneous injection at 8 mg/kg bodyweight in four rhesus monkeys (Macaca mulatta) and sensitivity of bacterial isolates from fresh skin...... wounds were determined. After administration, blood, urine, and feces were collected, and concentrations of cefovecin were determined. Further, the minimum inhibitory concentrations (MIC) for bacteria isolated from fresh skin wounds of monkeys during a health control program were determined. The mean...... maximum plasma concentration (C(max) ) of cefovecin was 78 µg/mL and was achieved after 57 min. The mean apparent long elimination half-life (t½) was 6.6 h and excretion occurred mainly via urine. The MIC for the majority of the bacteria examined was >100 µg/mL. The PK of cefovecin in rhesus monkeys...

Canine Distemper Outbreak in Rhesus Monkeys, China

Science.gov (United States)

Qiu, Wei; Zheng, Ying; Zhang, Shoufeng; Fan, Quanshui; Liu, Hua; Zhang, Fuqiang; Wang, Wei; Liao, Guoyang

2011-01-01

Since 2006, canine distemper outbreaks have occurred in rhesus monkeys at a breeding farm in Guangxi, People’s Republic of China. Approximately 10,000 animals were infected (25%–60% disease incidence); 5%–30% of infected animals died. The epidemic was controlled by vaccination. Amino acid sequence analysis of the virus indicated a unique strain. PMID:21801646

B cell follicle sanctuary permits persistent productive simian immunodeficiency virus infection in elite controllers.

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Fukazawa, Yoshinori; Lum, Richard; Okoye, Afam A; Park, Haesun; Matsuda, Kenta; Bae, Jin Young; Hagen, Shoko I; Shoemaker, Rebecca; Deleage, Claire; Lucero, Carissa; Morcock, David; Swanson, Tonya; Legasse, Alfred W; Axthelm, Michael K; Hesselgesser, Joseph; Geleziunas, Romas; Hirsch, Vanessa M; Edlefsen, Paul T; Piatak, Michael; Estes, Jacob D; Lifson, Jeffrey D; Picker, Louis J

2015-02-01

Chronic-phase HIV and simian immunodeficiency virus (SIV) replication is reduced by as much as 10,000-fold in elite controllers (ECs) compared with typical progressors (TPs), but sufficient viral replication persists in EC tissues to allow viral sequence evolution and induce excess immune activation. Here we show that productive SIV infection in rhesus monkey ECs, but not TPs, is markedly restricted to CD4(+) follicular helper T (TFH) cells, suggesting that these EC monkeys' highly effective SIV-specific CD8(+) T cells can effectively clear productive SIV infection from extrafollicular sites, but their relative exclusion from B cell follicles prevents their elimination of productively infected TFH cells. CD8(+) lymphocyte depletion in EC monkeys resulted in a dramatic re-distribution of productive SIV infection to non-TFH cells, with restriction of productive infection to TFH cells resuming upon CD8(+) T cell recovery. Thus, B cell follicles constitute 'sanctuaries' for persistent SIV replication in the presence of potent anti-viral CD8(+) T cell responses, potentially complicating efforts to cure HIV infection with therapeutic vaccination or T cell immunotherapy.

Durable protection of rhesus macaques immunized with a replicating adenovirus-SIV multigene prime/protein boost vaccine regimen against a second SIVmac251 rectal challenge: role of SIV-specific CD8+ T cell responses.

Science.gov (United States)

Malkevitch, Nina V; Patterson, L Jean; Aldrich, M Kristine; Wu, Yichen; Venzon, David; Florese, Ruth H; Kalyanaraman, V S; Pal, Ranajit; Lee, Eun Mi; Zhao, Jun; Cristillo, Anthony; Robert-Guroff, Marjorie

2006-09-15

Previously, priming with replication-competent adenovirus-SIV multigenic vaccines and boosting with envelope subunits strongly protected 39% of rhesus macaques against rectal SIV(mac251) challenge. To evaluate protection durability, eleven of the protected and two SIV-infected unimmunized macaques that controlled viremia were re-challenged rectally with SIV(mac251). Strong protection was observed in 8/11 vaccinees, including two exhibiting protected macaques. Durable protection was associated with significantly increased SIV-specific ELISPOT responses and lymphoproliferative responses to p27 at re-challenge. After CD8 depletion, 2 of 8 re-challenged, protected vaccinees maintained protection against re-challenge.

Altered regional homogeneity of brain spontaneous signals in SIV infected rhesus macaque model.

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Zhao, Jing; Jing, Bin; Chen, Feng; Liu, Jiaojiao; Wang, Yuanyuan; Li, Hongjun

2017-04-01

Regional homogeneity (ReHo), a measurement from resting-state functional magnetic imaging (rs-fMRI) to reflect local synchronization of brain activities, has been widely explored in previous studies of neurological diseases. SIV infected model for detecting the neurological changes with progression was studied. In the study, six rhesus macaques infected by simian immunodeficiency virus (SIV) were scanned by resting-state fMRI at the following time points: before SIV inoculation (baseline), 12weeks and 24weeks post inoculation (12wpi, 24wpi). Meanwhile, the immunological parameters including serum percentage of CD4+ T cell, CD4/CD8 ratio and absolute CD4+ T cell number were measured and analyzed. In comparison of baseline, significant decreased ReHo was found in the left superior frontal gyrus, left superior temporal gyrus, left hippocampus, right precuneus, left angular gyrus, and bilateral occipital gyrus; in contrast increased ReHo in putamen at 12wpi. Moreover, at the time of 24wpi, decreased ReHo was observed in the right postcentral gyrus, left precentral gyrus, posterior cingulated gyrus and thalamus, while ReHo was increased in the left putamen, hippocampus, left anterior cingulated cortex and precentral cortex. The correlation analysis revealed that ReHo in the superior frontal gyrus showed negative association with CD4/CD8 ratio and positive with absolute CD4+ T cell number. The correlation analysis showed that percentage of CD4+ was correlated with the ReHo values in right middle frontal gyrus, bilateral thalamus and amygdala positively; negative relationship with left putamen, left superior frontal gyrus, left superior and middle temporal gyrus. The study first indicates that hippocampus, putamen, frontal and occipital lobe were impaired by using rs-fMRI and correlated with immunological parameters. Thus, ReHo value can be utilized as a noninvasive biomarker of spontaneous brain activity changes caused by the progression of neurological impairments

Low dose rectal inoculation of rhesus macaques by SIV smE660 or SIVmac251 recapitulates

Energy Technology Data Exchange (ETDEWEB)

Hraber, Peter [Los Alamos National Laboratory; Giorgi, Elena E [Los Alamos National Laboratory; Keele, Brandon [UNIV OF ALABAMA; Li, Hui [UNIV OF ALABAMA; Learn, Gerald [UNIV OF ALABAMA

2008-01-01

We recently developed a novel strategy to identify transmitted HIV-1 genomes in acutely infected humans using single-genome amplification and a model of random virus evolution. Here, we used this approach to determine the molecular features of simian immunodeficiency virus (SIV) transmission in 18 experimentally infected Indian rhesus macaques. Animals were inoculated intrarectally (i.r.) or intravenously (i.v.) with stocks of SIVmac251 or SIVsmE660 that exhibited sequence diversity typical of early-chronic HIV-1 infection. 987 full-length SIV env sequences (median of 48 per animal) were determined from plasma virion RNA 1--5 wk after infection. i.r. inoculation was followed by productive infection by one or a few viruses (median 1; range 1--5) that diversified randomly with near starlike phylogeny and a Poisson distribution of mutations. Consensus viral sequences from ramp-up and peak viremia were identical to viruses found in the inocula or differed from them by only one or a few nucleotides, providing direct evidence that early plasma viral sequences coalesce to transmitted/founder viruses. i.v. infection was >2,000-fold more efficient than i.r. infection, and viruses transmitted by either route represented the full genetic spectra of the inocula. These findings identify key similarities in mucosal transmission and early diversification between SIV and HIV-1, and thus validate the SIV-macaque mucosal infection model for HIV-1 vaccine and microbicide research.

Safety and tolerability of a live oral Salmonella typhimurium vaccine candidate in SIV-infected nonhuman primates.

Science.gov (United States)

Ault, Alida; Tennant, Sharon M; Gorres, J Patrick; Eckhaus, Michael; Sandler, Netanya G; Roque, Annelys; Livio, Sofie; Bao, Saran; Foulds, Kathryn E; Kao, Shing-Fen; Roederer, Mario; Schmidlein, Patrick; Boyd, Mary Adetinuke; Pasetti, Marcela F; Douek, Daniel C; Estes, Jacob D; Nabel, Gary J; Levine, Myron M; Rao, Srinivas S

2013-12-02

Nontyphoidal Salmonella (NTS) serovars are a common cause of acute food-borne gastroenteritis worldwide and can cause invasive systemic disease in young infants, the elderly, and immunocompromised hosts, accompanied by high case fatality. Vaccination against invasive NTS disease is warranted where the disease incidence and mortality are high and multidrug resistance is prevalent, as in sub-Saharan Africa. Live-attenuated vaccines that mimic natural infection constitute one strategy to elicit protection. However, they must particularly be shown to be adequately attenuated for consideration of immunocompromised subjects. Accordingly, we examined the safety and tolerability of an oral live attenuated Salmonella typhimurium vaccine candidate, CVD 1921, in an established chronic simian immunodeficiency virus (SIV)-infected rhesus macaque model. We evaluated clinical parameters, histopathology, and measured differences in mucosal permeability to wild-type and vaccine strains. Compared to the wild-type S. typhimurium strain I77 in both SIV-infected and SIV-uninfected nonhuman primate hosts, this live-attenuated vaccine shows reduced shedding and systemic spread, exhibits limited pathological disease manifestations in the digestive tract, and induces low levels of cellular infiltration in tissues. Furthermore, wild-type S. typhimurium induces increased intestinal epithelial damage and permeability, with infiltration of neutrophils and macrophages in both SIV-infected and SIV-uninfected nonhuman primates compared to the vaccine strain. Based on shedding, systemic spread, and histopathology, the live-attenuated S. typhimurium strain CVD 1921 appears to be safe and well-tolerated in the nonhuman primate model, including chronically SIV-infected rhesus macaques. Copyright © 2013. Published by Elsevier Ltd.

Molecular characterization of Blastocystis isolates from children and rhesus monkeys in Kathmandu, Nepal.

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Yoshikawa, Hisao; Wu, Zhiliang; Pandey, Kishor; Pandey, Basu Dev; Sherchand, Jeevan Bahadur; Yanagi, Tetsuo; Kanbara, Hiroji

2009-03-23

To investigate the possible transmission of Blastocystis organisms between local rhesus monkeys and children in Kathmandu, Nepal, we compared the subtype (ST) and sequence of Blastocystis isolates from children with gastrointestinal symptoms and local rhesus monkeys. Twenty and 10 Blastocystis isolates were established from 82 and 10 fecal samples obtained from children and monkeys, respectively. Subtype analysis with seven sequence-tagged site (STS) primers indicated that the prevalence of Blastocystis sp. ST1, ST2 and ST3 was 20%, 20% and 60% in the child isolates, respectively. In contrast to human isolates, ST3 was not found in monkey isolates and the prevalence of ST1 and ST2 was 50% and 70%, respectively, including three mixed STs1 and 2 and one isolate not amplified by any STS primers, respectively. Since Blastocystis sp. ST2 has been reported as the most dominant genotype in the survey of Blastocystis infection among the various monkey species, sequence comparison of the 150bp variable region of the small subunit rRNA (SSU rRNA) gene was conducted among ST2 isolates of humans and monkeys. Sequence alignment of 24 clones developed from ST2 isolates of 4 humans and 4 monkeys showed three distinct subgroups, defined as ST2A, ST2B and ST2C. These three subgroups were shared between the child and monkey isolates. These results suggest that the local rhesus monkeys are a possible source of Blastocystis sp. ST2 infection of humans in Kathmandu.

Epidurography with metrizamide in Rhesus monkeys

International Nuclear Information System (INIS)

Kido, D.K.; Baker, R.A.; Saubermann, A.; Salem, J.; Schoene, W.C.; Fournier, P.

1980-01-01

Epidurography with metrizamide was performed on 9 Rhesus monkeys; physiologic saline was substituted for metrizamide in 3 control monkeys. Metrizamide successfully outlined the epidural space without causing any adverse clinical effects or direct tissue injury. (Auth.)

Pathogenesis of Rift Valley Fever in Rhesus Monkeys: Role of Interferon Response

Science.gov (United States)

1990-01-01

hemorrhagic fever characterized by epistaxis, petechial to purpuric cutaneous lesions, anorexia, and vomiting prior to death. The 14 remaining monkeys survived...DMI, FILE Copy Arch Virol (1990) 110: 195-212 Amhivesirology ( by Springer-Verlag 1990 00 N Pathogenesis of Rift Valley fever in rhesus monkeys: (NI...inoculated intravenously with Rift Valley fever (RVF) virus presented clinical disease syndromes similar to human cases of RVF. All 17 infected monkeys

Reference values of clinical chemistry and hematology parameters in rhesus monkeys (Macaca mulatta).

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Chen, Younan; Qin, Shengfang; Ding, Yang; Wei, Lingling; Zhang, Jie; Li, Hongxia; Bu, Hong; Lu, Yanrong; Cheng, Jingqiu

2009-01-01

Rhesus monkey models are valuable to the studies of human biology. Reference values for clinical chemistry and hematology parameters of rhesus monkeys are required for proper data interpretation. Whole blood was collected from 36 healthy Chinese rhesus monkeys (Macaca mulatta) of either sex, 3 to 5 yr old. Routine chemistry and hematology parameters, and some special coagulation parameters including thromboelastograph and activities of coagulation factors were tested. We presented here the baseline values of clinical chemistry and hematology parameters in normal Chinese rhesus monkeys. These data may provide valuable information for veterinarians and investigators using rhesus monkeys in experimental studies.

Effects of treatment with suppressive combination antiretroviral drug therapy and the histone deacetylase inhibitor suberoylanilide hydroxamic acid; (SAHA on SIV-infected Chinese rhesus macaques.

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Binhua Ling

Full Text Available Viral reservoirs-persistent residual virus despite combination antiretroviral therapy (cART-remain an obstacle to cure of HIV-1 infection. Difficulty studying reservoirs in patients underscores the need for animal models that mimics HIV infected humans on cART. We studied SIV-infected Chinese-origin rhesus macaques (Ch-RM treated with intensive combination antiretroviral therapy (cART and 3 weeks of treatment with the histone deacetyalse inhibitor, suberoylanilide hydroxamic acid (SAHA.SIVmac251 infected Ch-RM received reverse transcriptase inhibitors PMPA and FTC and integrase inhibitor L-870812 beginning 7 weeks post infection. Integrase inhibitor L-900564 and boosted protease inhibitor treatment with Darunavir and Ritonavir were added later. cART was continued for 45 weeks, with daily SAHA administered for the last 3 weeks, followed by euthanasia/necropsy. Plasma viral RNA and cell/tissue-associated SIV gag RNA and DNA were quantified by qRT-PCR/qPCR, with flow cytometry monitoring changes in immune cell populations.Upon cART initiation, plasma viremia declined, remaining <30 SIV RNA copy Eq/ml during cART, with occasional blips. Decreased viral replication was associated with decreased immune activation and partial restoration of intestinal CD4+ T cells. SAHA was well tolerated but did not result in demonstrable treatment-associated changes in plasma or cell associated viral parameters.The ability to achieve and sustain virological suppression makes cART-suppressed, SIV-infected Ch-RM a potentially useful model to evaluate interventions targeting residual virus. However, despite intensive cART over one year, persistent viral DNA and RNA remained in tissues of all three animals. While well tolerated, three weeks of SAHA treatment did not demonstrably impact viral RNA levels in plasma or tissues; perhaps reflecting dosing, sampling and assay limitations.

A Multiplex Microsphere-Based Immunoassay Increases the Sensitivity of SIV-Specific Antibody Detection in Serum Samples and Mucosal Specimens Collected from Rhesus Macaques Infected with SIVmac239.

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Powell, Rebecca L R; Ouellette, Ian; Lindsay, Ross W; Parks, Christopher L; King, C Richter; McDermott, Adrian B; Morrow, Gavin

2013-06-01

Results from recent HIV-1 vaccine studies have indicated that high serum antibody (Ab) titers may not be necessary for Ab-mediated protection, and that Abs localized to mucosal sites might be critical for preventing infection. Enzyme-linked immunosorbent assay (ELISA) has been used for decades as the gold standard for Ab measurement, though recently, highly sensitive microsphere-based assays have become available, with potential utility for improved detection of Abs. In this study, we assessed the Bio-Plex(®) Suspension Array System for the detection of simian immunodeficiency virus (SIV)-specific Abs in rhesus macaques (RMs) chronically infected with SIV, whose serum or mucosal SIV-specific Ab titers were negative by ELISA. We developed a SIVmac239-specific 4-plex bead array for the simultaneous detection of Abs binding to Env, Gag, Pol, and Nef. The 4-plex assay was used to quantify SIV-specific serum IgG and rectal swab IgA titers from control (SIV-naive) and SIVmac239-infected RMs. The Bio-Plex assay specifically detected anti-SIV Abs in specimens from SIV-infected animals for all four analytes when compared to SIV-naive control samples (p≤0.04). Furthermore, in 70% of Env and 79% of Gag ELISA-negative serum samples, specific Ab was detected using the Bio-Plex assay. Similarly, 71% of Env and 48% of Gag ELISA-negative rectal swab samples were identified as positive using the Bio-Plex assay. Importantly, assay specificity (i.e., probability of true positives) was comparable to ELISA (94%-100%). The results reported here indicate that microsphere-based methods provide a substantial improvement over ELISA for the detection of Ab responses, aid in detecting specific Abs when analyzing samples containing low levels of Abs, such as during the early stages of a vaccine trial, and may be valuable in attempts to link protective efficacy of vaccines with induced Ab responses.

Global gene expression analysis of peripheral blood mononuclear cells in rhesus monkey infants with CA16 infection-induced HFMD.

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Song, Jie; Hu, Yajie; Hu, Yunguang; Wang, Jingjing; Zhang, Xiaolong; Wang, Lichun; Guo, Lei; Wang, Yancui; Ning, Ruotong; Liao, Yun; Zhang, Ying; Zheng, Huiwen; Shi, Haijing; He, Zhanlong; Li, Qihan; Liu, Longding

2016-03-02

Coxsackievirus A16 (CA16) is a dominant pathogen that results in hand, foot, and mouth disease and causes outbreaks worldwide, particularly in the Asia-Pacific region. However, the underlying molecular mechanisms remain unclear. Our previous study has demonstrated that the basic CA16 pathogenic process was successfully mimicked in rhesus monkey infant. The present study focused on the global gene expression changes in peripheral blood mononuclear cells of rhesus monkey infants with hand, foot, and mouth disease induced by CA16 infection at different time points. Genome-wide expression analysis was performed with Agilent whole-genome microarrays and established bioinformatics tools. Nine hundred and forty-eight significant differentially expressed genes that were associated with 5 gene ontology categories, including cell communication, cell cycle, immune system process, regulation of transcription and metabolic process were identified. Subsequently, the mapping of genes related to the immune system process by PANTHER pathway analysis revealed the predominance of inflammation mediated by chemokine and cytokine signaling pathways and the interleukin signaling pathway. Ultimately, co-expressed genes and their networks were analyzed. The results revealed the gene expression profile of the immune system in response to CA16 in rhesus monkey infants and suggested that such an immune response was generated as a result of the positive mobilization of the immune system. This initial microarray study will provide insights into the molecular mechanism of CA16 infection and will facilitate the identification of biomarkers for the evaluation of vaccines against this virus. Copyright © 2016 Elsevier B.V. All rights reserved.

Comparative Infectivity Determinations of Dengue Virus Vaccine Candidates in Rhesus Monkeys, Mosquitoes, and Cell Cultures

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1993-01-28

34 are required for the evaluation of these vaccine candidates. RE: DAMDI7-89-C-9175 Page 16 REFERENCES 1. Sabin AB, Sclesinger RW, 1945. Production of...AD-A261 892 CONTRACT NO: DAMD17-89-C-9 175 \\II\\IllI\\I\\I1\\\\~il\\ TITLE: COMPARATIVE INFECTIVITY DETERMINATIONS OF DENGUE VIRUS VACCINE CANDIDATES IN... Vaccine Candidates in Rhesus Monkeys, 63002A Mosquitoes, and Cell Cultures 3M263002D870 AC 6. AUTHOR(S) DA335475 Edmundo Kraiselburd 7. PERFORMING

Construction and evaluation of novel rhesus monkey adenovirus vaccine vectors.

Science.gov (United States)

Abbink, Peter; Maxfield, Lori F; Ng'ang'a, David; Borducchi, Erica N; Iampietro, M Justin; Bricault, Christine A; Teigler, Jeffrey E; Blackmore, Stephen; Parenteau, Lily; Wagh, Kshitij; Handley, Scott A; Zhao, Guoyan; Virgin, Herbert W; Korber, Bette; Barouch, Dan H

2015-02-01

Adenovirus vectors are widely used as vaccine candidates for a variety of pathogens, including HIV-1. To date, human and chimpanzee adenoviruses have been explored in detail as vaccine vectors. The phylogeny of human and chimpanzee adenoviruses is overlapping, and preexisting humoral and cellular immunity to both are exhibited in human populations worldwide. More distantly related adenoviruses may therefore offer advantages as vaccine vectors. Here we describe the primary isolation and vectorization of three novel adenoviruses from rhesus monkeys. The seroprevalence of these novel rhesus monkey adenovirus vectors was extremely low in sub-Saharan Africa human populations, and these vectors proved to have immunogenicity comparable to that of human and chimpanzee adenovirus vaccine vectors in mice. These rhesus monkey adenoviruses phylogenetically clustered with the poorly described adenovirus species G and robustly stimulated innate immune responses. These novel adenoviruses represent a new class of candidate vaccine vectors. Although there have been substantial efforts in the development of vaccine vectors from human and chimpanzee adenoviruses, far less is known about rhesus monkey adenoviruses. In this report, we describe the isolation and vectorization of three novel rhesus monkey adenoviruses. These vectors exhibit virologic and immunologic characteristics that make them attractive as potential candidate vaccine vectors for both HIV-1 and other pathogens. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Induction of encephalitis in rhesus monkeys infused with lymphocryptovirus-infected B-cells presenting MOG(34-56 peptide.

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Krista G Haanstra

Full Text Available The overlapping epidemiology of multiple sclerosis (MS and Epstein-Barr virus (EBV, the increased risk to develop MS after infectious mononucleosis (IM and the localization of EBV-infected B-cells within the MS brain suggest a causal link between EBV and MS. However, the underlying mechanism is unknown. We hypothesize that EBV-infected B-cells are capable of eliciting a central nervous system (CNS targeting autoimmune reaction. To test this hypothesis we have developed a novel experimental model in rhesus monkeys of IM-like disease induced by infusing autologous B-lymphoblastoid cells (B-LCL. Herpesvirus papio (HVP is a lymphocryptovirus related to EBV and was used to generate rhesus monkey B-LCL. Three groups of five animals were included; each group received three intravenous infusions of B-LCL that were either pulsed with the encephalitogenic self peptide MOG(34-56 (group A, a mimicry peptide (981-1003 of the major capsid protein of cytomegalovirus (CMVmcp(981-1003; group B or the citrullinated MOG(34-56 (cMOG(34-56; group C. Groups A and B received on day 98 a single immunization with MOG(34-56 in incomplete Freund's adjuvant (IFA. Group C monkeys were euthanized just prior to day 98 without booster immunization. We observed self-peptide-specific proliferation of T-cells, superimposed on similar strong proliferation of CD3(+CD8(+ T-cells against the B-LCL as observed in IM. The brains of several monkeys contained perivascular inflammatory lesions of variable size, comprising CD3(+ and CD68(+ cells. Moreover, clusters of CD3(+ and CD20(+ cells were detected in the meninges. The only evident clinical sign was substantial loss of bodyweight (>15%, a symptom observed both in early autoimmune encephalitis and IM. In conclusion, this model suggests that EBV-induced B-LCL can elicit a CNS targeting inflammatory (autoimmune reaction.

Newly Identified CYP2C93 Is a Functional Enzyme in Rhesus Monkey, but Not in Cynomolgus Monkey

OpenAIRE

Uno, Yasuhiro; Uehara, Shotaro; Kohara, Sakae; Iwasaki, Kazuhide; Nagata, Ryoichi; Fukuzaki, Koichiro; Utoh, Masahiro; Murayama, Norie; Yamazaki, Hiroshi

2011-01-01

Cynomolgus monkey and rhesus monkey are used in drug metabolism studies due to their evolutionary closeness and physiological resemblance to human. In cynomolgus monkey, we previously identified cytochrome P450 (P450 or CYP) 2C76 that does not have a human ortholog and is partly responsible for species differences in drug metabolism between cynomolgus monkey and human. In this study, we report characterization of CYP2C93 cDNA newly identified in cynomolgus monkey and rhesus monkey. The CYP2C9...

A preliminary report on oral fat tolerance test in rhesus monkeys

OpenAIRE

Wu, Di; Liu, Qingsu; Wei, Shiyuan; Zhang, Yu Alex; Yue, Feng

2014-01-01

Background Oral fat tolerance test (OFTT) has been widely used to assess the postprandial lipemia in human beings, but there is few studies concerning OFTT in nonhuman primates. This study is designed to explore the feasibility of OFTT in rhesus monkeys. Methods In a cross-over study, a total of 8 adult female rhesus monkeys were fed with normal monkey diet (NND), high sugar high fat diet (HHD), and extremely high fat diet (EHD), respectively. Each monkey consumed NND, HHD and EHD respectivel...

Inducible nitric oxide synthase in heart tissue and nitric oxide in serum of Trypanosoma cruzi-infected rhesus monkeys: association with heart injury.

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Cristiano Marcelo Espinola Carvalho

Full Text Available BACKGROUND: The factors contributing to chronic Chagas' heart disease remain unknown. High nitric oxide (NO levels have been shown to be associated with cardiomyopathy severity in patients. Further, NO produced via inducible nitric oxide synthase (iNOS/NOS2 is proposed to play a role in Trypanosoma cruzi control. However, the participation of iNOS/NOS2 and NO in T. cruzi control and heart injury has been questioned. Here, using chronically infected rhesus monkeys and iNOS/NOS2-deficient (Nos2(-/- mice we explored the participation of iNOS/NOS2-derived NO in heart injury in T. cruzi infection. METHODOLOGY: Rhesus monkeys and C57BL/6 and Nos2(-/- mice were infected with the Colombian T. cruzi strain. Parasite DNA was detected by polymerase chain reaction, T. cruzi antigens and iNOS/NOS2(+ cells were immunohistochemically detected in heart sections and NO levels in serum were determined by Griess reagent. Heart injury was assessed by electrocardiogram (ECG, echocardiogram (ECHO, creatine kinase heart isoenzyme (CK-MB activity levels in serum and connexin 43 (Cx43 expression in the cardiac tissue. RESULTS: Chronically infected monkeys presented conduction abnormalities, cardiac inflammation and fibrosis, which resembled the spectrum of human chronic chagasic cardiomyopathy (CCC. Importantly, chronic myocarditis was associated with parasite persistence. Moreover, Cx43 loss and increased CK-MB activity levels were primarily correlated with iNOS/NOS2(+ cells infiltrating the cardiac tissue and NO levels in serum. Studies in Nos2(-/- mice reinforced that the iNOS/NOS2-NO pathway plays a pivotal role in T. cruzi-elicited cardiomyocyte injury and in conduction abnormalities that were associated with Cx43 loss in the cardiac tissue. CONCLUSION: T. cruzi-infected rhesus monkeys reproduce features of CCC. Moreover, our data support that in T. cruzi infection persistent parasite-triggered iNOS/NOS2 in the cardiac tissue and NO overproduction might contribute

Immunological alterations and associated diseases in mandrills (Mandrillus sphinx) naturally co-infected with SIV and STLV.

Science.gov (United States)

Souquière, Sandrine; Makuwa, Maria; Sallé, Bettina; Lepelletier, Yves; Mortreux, Franck; Hermine, Olivier; Kazanji, Mirdad

2014-04-01

Mandrills are naturally infected with simian T-cell leukaemia virus type 1 (STLV-1) and simian immunodeficiency virus (SIV)mnd. In humans, dual infection with human immunodeficiency virus (HIV) and human T-cell lymphotropic virus type 1 (HTLV-1) may worsen their clinical outcome. We evaluated the effect of co-infection in mandrills on viral burden, changes in T-cell subsets and clinical outcome. The SIV viral load was higher in SIV-infected mandrills than in co-infected animals, whereas the STLV-1 proviral load was higher in co-infected than in mono-infected groups. Dually infected mandrills had a statistically significantly lower CD4+ T-cell count, a lower proportion of naive CD8+ T cells and a higher proportion of central memory cells. CD4(+) and CD8(+) T cells from SIV-infected animals had a lower percentage of Ki67 than those from the other groups. Co-infected monkeys had higher percentages of activated CD4(+) and CD8(+) T cells. Two co-infected mandrills with high immune activation and clonal integration of STLV provirus showed pathological manifestations (infective dermatitis and generalised scabies) rarely encountered in nonhuman primates. Copyright © 2014 Elsevier Inc. All rights reserved.

Tonal frequency affects amplitude but not topography of rhesus monkey cranial EEG components.

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Teichert, Tobias

2016-06-01

The rhesus monkey is an important model of human auditory function in general and auditory deficits in neuro-psychiatric diseases such as schizophrenia in particular. Several rhesus monkey studies have described homologs of clinically relevant auditory evoked potentials such as pitch-based mismatch negativity, a fronto-central negativity that can be observed when a series of regularly repeating sounds is disrupted by a sound of different tonal frequency. As a result it is well known how differences of tonal frequency are represented in rhesus monkey EEG. However, to date there is no study that systematically quantified how absolute tonal frequency itself is represented. In particular, it is not known if frequency affects rhesus monkey EEG component amplitude and topography in the same way as previously shown for humans. A better understanding of the effect of frequency may strengthen inter-species homology and will provide a more solid foundation on which to build the interpretation of frequency MMN in the rhesus monkey. Using arrays of up to 32 cranial EEG electrodes in 4 rhesus macaques we identified 8 distinct auditory evoked components including the N85, a fronto-central negativity that is the presumed homolog of the human N1. In line with human data, the amplitudes of most components including the N85 peaked around 1000 Hz and were strongly attenuated above ∼1750 Hz. Component topography, however, remained largely unaffected by frequency. This latter finding may be consistent with the known absence of certain anatomical structures in the rhesus monkey that are believed to cause the changes in topography in the human by inducing a rotation of generator orientation as a function of tonal frequency. Overall, the findings are consistent with the assumption of a homolog representation of tonal frequency in human and rhesus monkey EEG. Copyright © 2016 Elsevier B.V. All rights reserved.

Turnover rates of B cells, T cells, and NK cells in simian immunodeficiency virus-infected and uninfected rhesus macaques

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Boer, R.J. de; Mohri, H.; Ho, D.D.; Perelson, A.S.

2003-01-01

We determined average cellular turnover rates by fitting mathematical models to 5-bromo-2'-deoxyuridine measurements in SIV-infected and uninfected rhesus macaques. The daily turnover rates of CD4(+) T cells, CD4(-) T cells, CD20(+) B cells, and CD16(+) NK cells in normal uninfected rhesus macaques

Association of TLR7 variants with AIDS-like disease and AIDS vaccine efficacy in rhesus macaques.

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Roman A Siddiqui

Full Text Available In HIV infection, TLR7-triggered IFN-α production exerts a direct antiviral effect through the inhibition of viral replication, but may also be involved in immune pathogenesis leading to AIDS. TLR7 could also be an important mediator of vaccine efficacy. In this study, we analyzed polymorphisms in the X-linked TLR7 gene in the rhesus macaque model of AIDS. Upon resequencing of the TLR7 gene in 36 rhesus macaques of Indian origin, 12 polymorphic sites were detected. Next, we identified three tightly linked single nucleotide polymorphisms (SNP as being associated with survival time. Genotyping of 119 untreated, simian immunodeficiency virus (SIV-infected male rhesus macaques, including an 'MHC adjusted' subset, revealed that the three TLR7 SNPs are also significantly associated with set-point viral load. Surprisingly, this effect was not observed in 72 immunized SIV-infected male monkeys. We hypothesize (i that SNP c.13G>A in the leader peptide is causative for the observed genotype-phenotype association and that (ii the underlying mechanism is related to RNA secondary structure formation. Therefore, we investigated a fourth SNP (c.-17C>T, located 17 bp upstream of the ATG translation initiation codon, that is also potentially capable of influencing RNA structure. In c.13A carriers, neither set-point viral load nor survival time were related to the c.-17C>T genotype. In c.13G carriers, by contrast, the c.-17C allele was significantly associated with prolonged survival. Again, no such association was detected among immunized SIV-infected macaques. Our results highlight the dual role of TLR7 in immunodeficiency virus infection and vaccination and imply that it may be important to control human AIDS vaccine trials, not only for MHC genotype, but also for TLR7 genotype.

Full-length cDNA sequences from Rhesus monkey placenta tissue: analysis and utility for comparative mapping

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Lee Sang-Rae

2010-07-01

Full Text Available Abstract Background Rhesus monkeys (Macaca mulatta are widely-used as experimental animals in biomedical research and are closely related to other laboratory macaques, such as cynomolgus monkeys (Macaca fascicularis, and to humans, sharing a last common ancestor from about 25 million years ago. Although rhesus monkeys have been studied extensively under field and laboratory conditions, research has been limited by the lack of genetic resources. The present study generated placenta full-length cDNA libraries, characterized the resulting expressed sequence tags, and described their utility for comparative mapping with human RefSeq mRNA transcripts. Results From rhesus monkey placenta full-length cDNA libraries, 2000 full-length cDNA sequences were determined and 1835 rhesus placenta cDNA sequences longer than 100 bp were collected. These sequences were annotated based on homology to human genes. Homology search against human RefSeq mRNAs revealed that our collection included the sequences of 1462 putative rhesus monkey genes. Moreover, we identified 207 genes containing exon alterations in the coding region and the untranslated region of rhesus monkey transcripts, despite the highly conserved structure of the coding regions. Approximately 10% (187 of all full-length cDNA sequences did not represent any public human RefSeq mRNAs. Intriguingly, two rhesus monkey specific exons derived from the transposable elements of AluYRa2 (SINE family and MER11B (LTR family were also identified. Conclusion The 1835 rhesus monkey placenta full-length cDNA sequences described here could expand genomic resources and information of rhesus monkeys. This increased genomic information will greatly contribute to the development of evolutionary biology and biomedical research.

Placental Transport of Zidovudine in the Rhesus Monkey

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Ridgway III, Louis E.; King, Thomas S.; Henderson, George I.; Schenker, Steven; Schenken, Robert S.

1993-01-01

Objective: This study was undertaken to characterize the pharmacokinetics of zidovudine (ZDV) and ZDV-glucuronide (ZDVG) in the material and :fetal circulations of the rhesus monkey. Methods: Cannulas were placed in the maternal external jugular and the fetal internal jugular and carotid artery in 8 pregnant monkeys at .120–130 days gestation. ZDV (3.5 mg/kg) was administered to 5 monkeys and ZDVG (3.5 mg/kg) to 3 monkeys as single intravenous bolus infusions through the maternal catheter. Ma...

Role of Monocyte/Macrophages during HIV/SIV Infection in Adult and Pediatric Acquired Immune Deficiency Syndrome

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Kristen M. Merino

2017-12-01

Full Text Available Monocytes/macrophages are a diverse group of cells that act as first responders in innate immunity and then as mediators for adaptive immunity to help clear infections. In performing these functions, however, the macrophage inflammatory responses can also contribute to pathogenesis. Various monocyte and tissue macrophage subsets have been associated with inflammatory disorders and tissue pathogeneses such as occur during HIV infection. Non-human primate research of simian immunodeficiency virus (SIV has been invaluable in better understanding the pathogenesis of HIV infection. The question of HIV/SIV-infected macrophages serving as a viral reservoir has become significant for achieving a cure. In the rhesus macaque model, SIV-infected macrophages have been shown to promote pathogenesis in several tissues resulting in cardiovascular, metabolic, and neurological diseases. Results from human studies illustrated that alveolar macrophages could be an important HIV reservoir and humanized myeloid-only mice supported productive HIV infection and viral persistence in macrophages during ART treatment. Depletion of CD4+ T cells is considered the primary cause for terminal progression, but it was reported that increasing monocyte turnover was a significantly better predictor in SIV-infected adult macaques. Notably, pediatric cases of HIV/SIV exhibit faster and more severe disease progression than adults, yet neonates have fewer target T cells and generally lack the hallmark CD4+ T cell depletion typical of adult infections. Current data show that the baseline blood monocyte turnover rate was significantly higher in neonatal macaques compared to adults and this remained high with disease progression. In this review, we discuss recent data exploring the contribution of monocytes and macrophages to HIV/SIV infection and progression. Furthermore, we highlight the need to further investigate their role in pediatric cases of infection.

Spontaneous Metacognition in Rhesus Monkeys.

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Rosati, Alexandra G; Santos, Laurie R

2016-09-01

Metacognition is the ability to think about thinking. Although monitoring and controlling one's knowledge is a key feature of human cognition, its evolutionary origins are debated. In the current study, we examined whether rhesus monkeys (Macaca mulatta; N = 120) could make metacognitive inferences in a one-shot decision. Each monkey experienced one of four conditions, observing a human appearing to hide a food reward in an apparatus consisting of either one or two tubes. The monkeys tended to search the correct location when they observed this baiting event, but engaged in information seeking-by peering into a center location where they could check both potential hiding spots-if their view had been occluded and information seeking was possible. The monkeys only occasionally approached the center when information seeking was not possible. These results show that monkeys spontaneously use information about their own knowledge states to solve naturalistic foraging problems, and thus provide the first evidence that nonhumans exhibit information-seeking responses in situations with which they have no prior experience. © The Author(s) 2016.

Induction of Encephalitis in Rhesus Monkeys Infused with Lymphocryptovirus-Infected B-Cells Presenting MOG34–56 Peptide

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Haanstra, Krista G.; Wubben, Jacqueline A. M.; Jonker, Margreet; Hart, Bert A. ‘t.

2013-01-01

The overlapping epidemiology of multiple sclerosis (MS) and Epstein-Barr virus (EBV), the increased risk to develop MS after infectious mononucleosis (IM) and the localization of EBV-infected B-cells within the MS brain suggest a causal link between EBV and MS. However, the underlying mechanism is unknown. We hypothesize that EBV-infected B-cells are capable of eliciting a central nervous system (CNS) targeting autoimmune reaction. To test this hypothesis we have developed a novel experimental model in rhesus monkeys of IM-like disease induced by infusing autologous B-lymphoblastoid cells (B-LCL). Herpesvirus papio (HVP) is a lymphocryptovirus related to EBV and was used to generate rhesus monkey B-LCL. Three groups of five animals were included; each group received three intravenous infusions of B-LCL that were either pulsed with the encephalitogenic self peptide MOG34–56 (group A), a mimicry peptide (981–1003) of the major capsid protein of cytomegalovirus (CMVmcp981–1003; group B) or the citrullinated MOG34–56 (cMOG34–56; group C). Groups A and B received on day 98 a single immunization with MOG34–56 in incomplete Freund’s adjuvant (IFA). Group C monkeys were euthanized just prior to day 98 without booster immunization. We observed self-peptide-specific proliferation of T-cells, superimposed on similar strong proliferation of CD3+CD8+ T-cells against the B-LCL as observed in IM. The brains of several monkeys contained perivascular inflammatory lesions of variable size, comprising CD3+ and CD68+ cells. Moreover, clusters of CD3+ and CD20+ cells were detected in the meninges. The only evident clinical sign was substantial loss of bodyweight (>15%), a symptom observed both in early autoimmune encephalitis and IM. In conclusion, this model suggests that EBV-induced B-LCL can elicit a CNS targeting inflammatory (auto)immune reaction. PMID:23977076

Δ9-Tetrahydrocannabinol (Δ9-THC) Promotes Neuroimmune-Modulatory MicroRNA Profile in Striatum of Simian Immunodeficiency Virus (SIV)-Infected Macaques.

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Simon, Liz; Song, Keijing; Vande Stouwe, Curtis; Hollenbach, Andrew; Amedee, Angela; Mohan, Mahesh; Winsauer, Peter; Molina, Patricia

2016-03-01

Cannabinoid administration before and after simian immunodeficiency virus (SIV)-inoculation ameliorated disease progression and decreased inflammation in male rhesus macaques. Δ9-tetrahydrocannabinol (Δ9-THC) did not increase viral load in brain tissue or produce additive neuropsychological impairment in SIV-infected macaques. To determine if the neuroimmunomodulation of Δ9-THC involved differential microRNA (miR) expression, miR expression in the striatum of uninfected macaques receiving vehicle (VEH) or Δ9-THC (THC) and SIV-infected macaques administered either vehicle (VEH/SIV) or Δ9-THC (THC/SIV) was profiled using next generation deep sequencing. Among the 24 miRs that were differentially expressed among the four groups, 16 miRs were modulated by THC in the presence of SIV. These 16 miRs were classified into four categories and the biological processes enriched by the target genes determined. Our results indicate that Δ9-THC modulates miRs that regulate mRNAs of proteins involved in 1) neurotrophin signaling, 2) MAPK signaling, and 3) cell cycle and immune response thus promoting an overall neuroprotective environment in the striatum of SIV-infected macaques. This is also reflected by increased Brain Derived Neurotrophic Factor (BDNF) and decreased proinflammatory cytokine expression compared to the VEH/SIV group. Whether Δ9-THC-mediated modulation of epigenetic mechanisms provides neuroprotection in other regions of the brain and during chronic SIV-infection remains to be determined.

Newly identified CYP2C93 is a functional enzyme in rhesus monkey, but not in cynomolgus monkey.

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Yasuhiro Uno

Full Text Available Cynomolgus monkey and rhesus monkey are used in drug metabolism studies due to their evolutionary closeness and physiological resemblance to human. In cynomolgus monkey, we previously identified cytochrome P450 (P450 or CYP 2C76 that does not have a human ortholog and is partly responsible for species differences in drug metabolism between cynomolgus monkey and human. In this study, we report characterization of CYP2C93 cDNA newly identified in cynomolgus monkey and rhesus monkey. The CYP2C93 cDNA contained an open reading frame of 490 amino acids approximately 84-86% identical to human CYP2Cs. CYP2C93 was located in the genomic region, which corresponded to the intergenic region in the human genome, indicating that CYP2C93 does not correspond to any human genes. CYP2C93 mRNA was expressed predominantly in the liver among 10 tissues analyzed. The CYP2C93 proteins heterologously expressed in Escherichia coli metabolized human CYP2C substrates, diclofenac, flurbiprofen, paclitaxel, S-mephenytoin, and tolbutamide. In addition to a normal transcript (SV1, an aberrantly spliced transcript (SV2 lacking exon 2 was identified, which did not give rise to a functional protein due to frameshift and a premature termination codon. Mini gene assay revealed that the genetic variant IVS2-1G>T at the splice site of intron 1, at least partly, accounted for the exon-2 skipping; therefore, this genotype would influence CYP2C93-mediated drug metabolism. SV1 was expressed in 6 of 11 rhesus monkeys and 1 of 8 cynomolgus monkeys, but the SV1 in the cynomolgus monkey was nonfunctional due to a rare null genotype (c.102T>del. These results suggest that CYP2C93 can play roles as a drug-metabolizing enzyme in rhesus monkeys (not in cynomolgus monkeys, although its relative contribution to drug metabolism has yet to be validated.

Selection and Pairing of ’Normal’ Rhesus Monkeys (Macaca mulatta) for Research.

Science.gov (United States)

1978-11-08

week intervals. Fecal bacteriological cultures did not detect any Salmonella or Shigella car- riers in the population. The male monkeys ranged in age...1Special Roert 78-6 LVEL•$ SELECTION AND PAIRING OF "NORMAL" RHESUS MONKEYS (Macaca mulatto) FOR RESEARC Matthew J. Kessler, James L. Kupper, James D...public release; distribution unlimited. SELECTION AND PAIRING OF "NORMAL" RHESUS MONKEYS (Macaca mulatta) FOR RESEARCH Matthew J. Kessler, James L

Homogeneous antibodies in lethally irradiated and autologous bone marrow reconstituted Rhesus monkeys

International Nuclear Information System (INIS)

Berg, P. Van Den; Radl, J.; Loewenberg, B.; Swart, A.C.W.

1976-01-01

Ten Rhesus monkeys were lethally irradiated and reconstituted with autologous bone marrow. During the restoration period, the animals were immunized with DNP-Rhesus albumin and IgA1lambda-10S human paraprotein. One or more transient homogenous immunoglobulin components appeared in sera of all experimental monkeys. In four animals, these homogeneous immunoglobulins were shown to be specific antibodies against DNP-Rhesus albumin. They gradually became as heterogeneous as those in control monkeys which were immunized but not irradiated and transplanted. The onset of the specific antibody response after immunization was slightly delayed in the experimental group. On determining the time necessary to reach normalization of the overall immunoglobulin levels and the normal heterogeneity of the immunoglobulin spectrum, it was found to be more than 1 year in most of the animals. (author)

Performance norms for a rhesus monkey neuropsychological testing battery: acquisition and long-term performance.

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Weed, M R; Taffe, M A; Polis, I; Roberts, A C; Robbins, T W; Koob, G F; Bloom, F E; Gold, L H

1999-10-25

A computerized behavioral battery based upon human neuropsychological tests (CANTAB, CeNeS, Cambridge, UK) has been developed to assess cognitive behaviors of rhesus monkeys. Monkeys reliably performed multiple tasks, providing long-term assessment of changes in a number of behaviors for a given animal. The overall goal of the test battery is to characterize changes in cognitive behaviors following central nervous system (CNS) manipulations. The battery addresses memory (delayed non-matching to sample, DNMS; spatial working memory, using a self-ordered spatial search task, SOSS), attention (intra-/extra-dimensional shift, ID/ED), motivation (progressive-ratio, PR), reaction time (RT) and motor coordination (bimanual task). As with human neuropsychological batteries, different tasks are thought to involve different neural substrates, and therefore performance profiles should assess function in particular brain regions. Monkeys were tested in transport cages, and responding on a touch sensitive computer monitor was maintained by food reinforcement. Parametric manipulations of several tasks demonstrated the sensitivity of performance to increases in task difficulty. Furthermore, the factors influencing difficulty for rhesus monkeys were the same as those shown to affect human performance. Data from this study represent performance of a population of healthy normal monkeys that will be used for comparison in subsequent studies of performance following CNS manipulations such as infection with simian immunodeficiency virus (NeuroAIDS) or drug administration.

Circulation of Campylobacter spp. in rhesus monkeys (Macaca mulatta held in captivity: a longitudinal study

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Márcia Cristina Ribeiro Andrade

2007-02-01

Full Text Available Campylobacteriosis is an extremely important zoonosis, circulating freely in the environment. In nonhuman primates kept in open facilities and bred for experimental purposes, the presence of Campylobacter spp. could cause severe damage to the production and interfere with the results of scientific research. In this paper, we assessed the circulation of Campylobacter spp. in a colony of clinically healthy rhesus monkeys (Macaca mulatta destined to research. The analysis was carried out during seven non-consecutive years. Data showed that despite several changes made in animal management along the studied years in order to control this zoonosis, reduction of bacterial charge did not occur. Significant differences among the age groups and sex were observed. Infants showed higher susceptibility than adult animals. In general males were more infected than females. Modifications adopted in the handling techniques need to be reviewed with the intent of improving the production, reducing bacterial infection of the stock and avoiding undesirable cross reactions in the research carried out with these animals. Therefore, this paper alerts professionals that work directly with captive rhesus monkeys about the risks of Campylobacter spp. infection and possible interference on the experimental procedures.

Risky business: rhesus monkeys exhibit persistent preferences for risky options.

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Xu, Eric R; Kralik, Jerald D

2014-01-01

Rhesus monkeys have been shown to prefer risky over safe options in experiential decision-making tasks. These findings might be due, however, to specific contextual factors, such as small amounts of fluid reward and minimal costs for risk-taking. To better understand the factors affecting decision-making under risk in rhesus monkeys, we tested multiple factors designed to increase the stakes including larger reward amounts, distinct food items rather than fluid reward, a smaller number of trials per session, and risky options with greater variation that also included non-rewarded outcomes. We found a consistent preference for risky options, except when the expected value of the safe option was greater than the risky option. Thus, with equivalent mean utilities between the safe and risky options, rhesus monkeys appear to have a robust preference for the risky options in a broad range of circumstances, akin to the preferences found in human children and some adults in similar tasks. One account for this result is that monkeys make their choices based on the salience of the largest payoff, without integrating likelihood and value across trials. A related idea is that they fail to override an impulsive tendency to select the option with the potential to obtain the highest possible outcome. Our results rule out strict versions of both accounts and contribute to an understanding of the diversity of risky decision-making among primates.

RepSox improves viability and regulates gene expression in rhesus monkey-pig interspecies cloned embryos.

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Zhu, Hai-Ying; Jin, Long; Guo, Qing; Luo, Zhao-Bo; Li, Xiao-Chen; Zhang, Yu-Chen; Xing, Xiao-Xu; Xuan, Mei-Fu; Zhang, Guang-Lei; Luo, Qi-Rong; Wang, Jun-Xia; Cui, Cheng-Du; Li, Wen-Xue; Cui, Zheng-Yun; Yin, Xi-Jun; Kang, Jin-Dan

2017-05-01

To investigate the effect of the small molecule, RepSox, on the expression of developmentally important genes and the pre-implantation development of rhesus monkey-pig interspecies somatic cell nuclear transfer (iSCNT) embryos. Rhesus monkey cells expressing the monomeric red fluorescent protein 1 which have a normal (42) chromosome complement, were used as donor cells to generate iSCNT embryos. RepSox increased the expression levels of the pluripotency-related genes, Oct4 and Nanog (p  0.05), this was not significant. RepSox can improve the developmental potential of rhesus monkey-pig iSCNT embryos by regulating the expression of pluripotency-related genes.

Stability of the Gorilla Microbiome Despite SIV Infection

OpenAIRE

Moeller, Andrew H.; Peeters, Martine; Ayouba, Ahidjo; Ngole, Eitel Mpoudi; Esteban, Amadine; Hahn, Beatrice H.; Ochman, Howard

2015-01-01

Simian Immunodeficiency Viruses (SIVs) have been discovered in over 45 primate species; however, the pathogenic potential of most SIV strains remains unknown due to difficulties inherent in observing wild populations. Because those SIV infections that are pathogenic have been shown to induce changes in the host's gut microbiome, monitoring the microbiota present in fecal samples can provide a noninvasive means for studying the effects of SIV infection on the health of wild-living primates. He...

Coxsackievirus A 16 infection does not interfere with the specific immune response induced by an enterovirus 71 inactivated vaccine in rhesus monkeys.

Science.gov (United States)

Wang, Jingjing; Qi, Sudong; Zhang, Xiaolong; Zhang, Ying; Liu, Longding; Che, Yanchun; He, Zhanlong; Zhao, Yuan; Lu, Shuaiyao; Yu, Wenhai; Li, Qihan

2014-07-31

Hand, foot and mouth disease is usually caused by enterovirus 71 (EV71) and coxsackievirus A 16 (CA16), which are members of the Picornaviridae family. In the present study, the characteristics of the immune response induced by an EV71 inactivated vaccine (made from human diploid cells) were explored in the presence of CA16 infection, based on the previously established neonatal rhesus monkey model. The typical clinical manifestations, including body temperature, viral viremia and virus shedding in the mouth, pharynx and feces, were characterized. A specific neutralizing antibody assay showed that the specific immune response induced by the EV71 inactivated vaccine was active against EV71 but not against CA16. No remarkable fluctuation in proinflammatory cytokine release was identified in the serum of immunized monkeys with EV71 vaccine and CA16 infections subsequently. The results showed that the specific immune response induced by the EV71 inactivated vaccine is effective against EV71 infection but is not affected by CA16 infection. Copyright © 2014 Elsevier Ltd. All rights reserved.

Molecular cloning and characterization of rhesus monkey platelet glycoprotein Ibα, a major ligand-binding subunit of GPIb-IX-V complex.

Science.gov (United States)

Qiao, Jianlin; Shen, Yang; Shi, Meimei; Lu, Yanrong; Cheng, Jingqiu; Chen, Younan

2014-05-01

Through binding to von Willebrand factor (VWF), platelet glycoprotein (GP) Ibα, the major ligand-binding subunit of the GPIb-IX-V complex, initiates platelet adhesion and aggregation in response to exposed VWF or elevated fluid-shear stress. There is little data regarding non-human primate platelet GPIbα. This study cloned and characterized rhesus monkey (Macaca Mullatta) platelet GPIbα. DNAMAN software was used for sequence analysis and alignment. N/O-glycosylation sites and 3-D structure modelling were predicted by online OGPET v1.0, NetOGlyc 1.0 Server and SWISS-MODEL, respectively. Platelet function was evaluated by ADP- or ristocetin-induced platelet aggregation. Rhesus monkey GPIbα contains 2,268 nucleotides with an open reading frame encoding 755 amino acids. Rhesus monkey GPIbα nucleotide and protein sequences share 93.27% and 89.20% homology respectively, with human. Sequences encoding the leucine-rich repeats of rhesus monkey GPIbα share strong similarity with human, whereas PEST sequences and N/O-glycosylated residues vary. The GPIbα-binding residues for thrombin, filamin A and 14-3-3ζ are highly conserved between rhesus monkey and human. Platelet function analysis revealed monkey and human platelets respond similarly to ADP, but rhesus monkey platelets failed to respond to low doses of ristocetin where human platelets achieved 76% aggregation. However, monkey platelets aggregated in response to higher ristocetin doses. Monkey GPIbα shares strong homology with human GPIbα, however there are some differences in rhesus monkey platelet activation through GPIbα engagement, which need to be considered when using rhesus monkey platelet to investigate platelet GPIbα function. Copyright © 2014 Elsevier Ltd. All rights reserved.

Protective effect and the therapeutic index of indralin in juvenile rhesus monkeys

International Nuclear Information System (INIS)

Vasin, Mikhail V.; Antipov, Vsevolod V.; Ushakov, Igor B.; Semenov, Leonid F.; Lapin, Boris A.; Suvorov, Nikolai N.; Ilyin, Leonid A.

2014-01-01

The radioprotective effect of indralin in rhesus monkeys was examined over 60 d following gamma irradiation. Male and female rhesus macaques (Macaca mulatta) 2-3-years-old and weighing 2.1-3.5 kg were used. Animals were exposed to total-body gamma irradiation from 60 Co at a dose of 6.8 Gy (lethal dose, 100% lethality over 30 days). Indralin (40-120 mg kg -1 ) was administered intramuscularly 5 min prior to radiation exposure. Indralin taken at a dose of 120 mg kg -1 protected five out of six monkeys (compared with the radiation control group, in which all 10 animals died). The average effective dose of indralin in the monkeys exposed to gamma irradiation for 30 min was equal to 77.3 (63.3-94.3) mg kg -1 , and the maximum tolerated dose of indralin administered to monkeys was 800 mg kg -1 . Indralin reduced radiation-induced injuries in macaques, thus resulting in a less severe course of acute radiation syndrome. Delayed and less pronounced manifestation of the haemorrhagic syndrome of the disease, and milder forms of both leukopenia and anaemia were also noted. The therapeutic index for indralin, expressed as the ratio of the maximum tolerated dose to the average effective dose, was equal to 10. Therefore, indralin has a significant radioprotective effect against radiation and has a high therapeutic index in rhesus monkeys. (author)

Allergic asthma induced in rhesus monkeys by house dust mite (Dermatophagoides farinae).

Science.gov (United States)

Schelegle, E S; Gershwin, L J; Miller, L A; Fanucchi, M V; Van Winkle, L S; Gerriets, J P; Walby, W F; Omlor, A M; Buckpitt, A R; Tarkington, B K; Wong, V J; Joad, J P; Pinkerton, K B; Wu, R; Evans, M J; Hyde, D M; Plopper, C G

2001-01-01

To establish whether allergic asthma could be induced experimentally in a nonhuman primate using a common human allergen, three female rhesus monkeys (Macaca mulatta) were sensitized with house dust mite (Dermatophagoides farinae) allergen (HDMA) by subcutaneous injection, followed by four intranasal sensitizations, and exposure to allergen aerosol 3 hours per day, 3 days per week for up to 13 weeks. Before aerosol challenge, all three monkeys skin-tested positive for HDMA. During aerosol challenge with HDMA, sensitized monkeys exhibited cough and rapid shallow breathing and increased airway resistance, which was reversed by albuterol aerosol treatment. Compared to nonsensitized monkeys, there was a fourfold reduction in the dose of histamine aerosol necessary to produce a 150% increase in airway resistance in sensitized monkeys. After aerosol challenge, serum levels of histamine were elevated in sensitized monkeys. Sensitized monkeys exhibited increased levels of HDMA-specific IgE in serum, numbers of eosinophils and exfoliated cells within lavage, and elevated CD25 expression on circulating CD4(+) lymphocytes. Intrapulmonary bronchi of sensitized monkeys had focal mucus cell hyperplasia, interstitial infiltrates of eosinophils, and thickening of the basement membrane zone. We conclude that a model of allergic asthma can be induced in rhesus monkeys using a protocol consisting of subcutaneous injection, intranasal instillation, and aerosol challenge with HDMA.

Species-specific activity of SIV Nef and HIV-1 Vpu in overcoming restriction by tetherin/BST2.

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Bin Jia

2009-05-01

Full Text Available Tetherin, also known as BST2, CD317 or HM1.24, was recently identified as an interferon-inducible host-cell factor that interferes with the detachment of virus particles from infected cells. HIV-1 overcomes this restriction by expressing an accessory protein, Vpu, which counteracts tetherin. Since lentiviruses of the SIV(smm/mac/HIV-2 lineage do not have a vpu gene, this activity has likely been assumed by other viral gene products. We found that deletion of the SIV(mac239 nef gene significantly impaired virus release in cells expressing rhesus macaque tetherin. Virus release could be restored by expressing Nef in trans. However, Nef was unable to facilitate virus release in the presence of human tetherin. Conversely, Vpu enhanced virus release in the presence of human tetherin, but not in the presence of rhesus tetherin. In accordance with the species-specificity of Nef in mediating virus release, SIV Nef downregulated cell-surface expression of rhesus tetherin, but did not downregulate human tetherin. The specificity of SIV Nef for rhesus tetherin mapped to four amino acids in the cytoplasmic domain of the molecule that are missing from human tetherin, whereas the specificity of Vpu for human tetherin mapped to amino acid differences in the transmembrane domain. Nef alleles of SIV(smm, HIV-2 and HIV-1 were also able to rescue virus release in the presence of both rhesus macaque and sooty mangabey tetherin, but were generally ineffective against human tetherin. Thus, the ability of Nef to antagonize tetherin from these Old World primates appears to be conserved among the primate lentiviruses. These results identify Nef as the viral gene product of SIV that opposes restriction by tetherin in rhesus macaques and sooty mangabeys, and reveal species-specificity in the activities of both Nef and Vpu in overcoming tetherin in their respective hosts.

Rhesus monkeys (Macaca mulatta) detect rhythmic groups in music, but not the beat.

Science.gov (United States)

Honing, Henkjan; Merchant, Hugo; Háden, Gábor P; Prado, Luis; Bartolo, Ramón

2012-01-01

It was recently shown that rhythmic entrainment, long considered a human-specific mechanism, can be demonstrated in a selected group of bird species, and, somewhat surprisingly, not in more closely related species such as nonhuman primates. This observation supports the vocal learning hypothesis that suggests rhythmic entrainment to be a by-product of the vocal learning mechanisms that are shared by several bird and mammal species, including humans, but that are only weakly developed, or missing entirely, in nonhuman primates. To test this hypothesis we measured auditory event-related potentials (ERPs) in two rhesus monkeys (Macaca mulatta), probing a well-documented component in humans, the mismatch negativity (MMN) to study rhythmic expectation. We demonstrate for the first time in rhesus monkeys that, in response to infrequent deviants in pitch that were presented in a continuous sound stream using an oddball paradigm, a comparable ERP component can be detected with negative deflections in early latencies (Experiment 1). Subsequently we tested whether rhesus monkeys can detect gaps (omissions at random positions in the sound stream; Experiment 2) and, using more complex stimuli, also the beat (omissions at the first position of a musical unit, i.e. the 'downbeat'; Experiment 3). In contrast to what has been shown in human adults and newborns (using identical stimuli and experimental paradigm), the results suggest that rhesus monkeys are not able to detect the beat in music. These findings are in support of the hypothesis that beat induction (the cognitive mechanism that supports the perception of a regular pulse from a varying rhythm) is species-specific and absent in nonhuman primates. In addition, the findings support the auditory timing dissociation hypothesis, with rhesus monkeys being sensitive to rhythmic grouping (detecting the start of a rhythmic group), but not to the induced beat (detecting a regularity from a varying rhythm).

Rhesus monkeys (Macaca mulatta detect rhythmic groups in music, but not the beat.

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Henkjan Honing

Full Text Available It was recently shown that rhythmic entrainment, long considered a human-specific mechanism, can be demonstrated in a selected group of bird species, and, somewhat surprisingly, not in more closely related species such as nonhuman primates. This observation supports the vocal learning hypothesis that suggests rhythmic entrainment to be a by-product of the vocal learning mechanisms that are shared by several bird and mammal species, including humans, but that are only weakly developed, or missing entirely, in nonhuman primates. To test this hypothesis we measured auditory event-related potentials (ERPs in two rhesus monkeys (Macaca mulatta, probing a well-documented component in humans, the mismatch negativity (MMN to study rhythmic expectation. We demonstrate for the first time in rhesus monkeys that, in response to infrequent deviants in pitch that were presented in a continuous sound stream using an oddball paradigm, a comparable ERP component can be detected with negative deflections in early latencies (Experiment 1. Subsequently we tested whether rhesus monkeys can detect gaps (omissions at random positions in the sound stream; Experiment 2 and, using more complex stimuli, also the beat (omissions at the first position of a musical unit, i.e. the 'downbeat'; Experiment 3. In contrast to what has been shown in human adults and newborns (using identical stimuli and experimental paradigm, the results suggest that rhesus monkeys are not able to detect the beat in music. These findings are in support of the hypothesis that beat induction (the cognitive mechanism that supports the perception of a regular pulse from a varying rhythm is species-specific and absent in nonhuman primates. In addition, the findings support the auditory timing dissociation hypothesis, with rhesus monkeys being sensitive to rhythmic grouping (detecting the start of a rhythmic group, but not to the induced beat (detecting a regularity from a varying rhythm.

Molecularly engineered live-attenuated chimeric West Nile/dengue virus vaccines protect rhesus monkeys from West Nile virus

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Pletnev, Alexander G.; St Claire, Marisa; Elkins, Randy; Speicher, Jim; Murphy, Brian R.; Chanock, Robert M.

2003-01-01

Two molecularly engineered, live-attenuated West Nile virus (WN) vaccine candidates were highly attenuated and protective in rhesus monkeys. The vaccine candidates are chimeric viruses (designated WN/DEN4) bearing the membrane precursor and envelope protein genes of WN on a backbone of dengue 4 virus (DEN4) with or without a deletion of 30 nucleotides (Δ30) in the 3' noncoding region of DEN4. Viremia in WN/DEN4- infected monkeys was reduced 100-fold compared to that in WN- or DEN4-infected monkeys. WN/DEN4-3'Δ30 did not cause detectable viremia, indicating that it is even more attenuated for monkeys. These findings indicate that chimerization itself and the presence of the Δ30 mutation independently contribute to the attenuation phenotype for nonhuman primates. Despite their high level of attenuation in monkeys, the chimeras induced a moderate-to-high titer of neutralizing antibodies and prevented viremia in monkeys challenged with WN. The more attenuated vaccine candidate, WN/DEN4-3'Δ30, will be evaluated first in our initial clinical studies

Simian varicella virus infection of rhesus macaques recapitulates essential features of varicella zoster virus infection in humans.

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Ilhem Messaoudi

2009-11-01

Full Text Available Simian varicella virus (SVV, the etiologic agent of naturally occurring varicella in primates, is genetically and antigenically closely related to human varicella zoster virus (VZV. Early attempts to develop a model of VZV pathogenesis and latency in nonhuman primates (NHP resulted in persistent infection. More recent models successfully produced latency; however, only a minority of monkeys became viremic and seroconverted. Thus, previous NHP models were not ideally suited to analyze the immune response to SVV during acute infection and the transition to latency. Here, we show for the first time that intrabronchial inoculation of rhesus macaques with SVV closely mimics naturally occurring varicella (chickenpox in humans. Infected monkeys developed varicella and viremia that resolved 21 days after infection. Months later, viral DNA was detected only in ganglia and not in non-ganglionic tissues. Like VZV latency in human ganglia, transcripts corresponding to SVV ORFs 21, 62, 63 and 66, but not ORF 40, were detected by RT-PCR. In addition, as described for VZV, SVV ORF 63 protein was detected in the cytoplasm of neurons in latently infected monkey ganglia by immunohistochemistry. We also present the first in depth analysis of the immune response to SVV. Infected animals produced a strong humoral and cell-mediated immune response to SVV, as assessed by immunohistology, serology and flow cytometry. Intrabronchial inoculation of rhesus macaques with SVV provides a novel model to analyze viral and immunological mechanisms of VZV latency and reactivation.

Rhesus monkey neural stem cell transplantation promotes neural regeneration in rats with hippocampal lesions

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Li-juan Ye

2016-01-01

Full Text Available Rhesus monkey neural stem cells are capable of differentiating into neurons and glial cells. Therefore, neural stem cell transplantation can be used to promote functional recovery of the nervous system. Rhesus monkey neural stem cells (1 × 105 cells/μL were injected into bilateral hippocampi of rats with hippocampal lesions. Confocal laser scanning microscopy demonstrated that green fluorescent protein-labeled transplanted cells survived and grew well. Transplanted cells were detected at the lesion site, but also in the nerve fiber-rich region of the cerebral cortex and corpus callosum. Some transplanted cells differentiated into neurons and glial cells clustering along the ventricular wall, and integrated into the recipient brain. Behavioral tests revealed that spatial learning and memory ability improved, indicating that rhesus monkey neural stem cells noticeably improve spatial learning and memory abilities in rats with hippocampal lesions.

Piracetam-induced changes on the brainstem auditory response in anesthetized juvenile rhesus monkeys (Macaca mulatta). Report of two clinical cases.

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Durand-Rivera, A; Gonzalez-Pina, R; Hernandez-Godinez, B; Ibanez-Contreras, A; Bueno-Nava, A; Alfaro-Rodriguez, A

2012-10-01

We describe two clinical cases and examine the effects of piracetam on the brainstem auditory response in infantile female rhesus monkeys (Macaca mulatta). We found that the interwave intervals show a greater reduction in a 3-year-old rhesus monkey compared to a 1-year-old rhesus monkey. In this report, we discuss the significance of these observations. © 2012 John Wiley & Sons A/S.

Stability of the Gorilla Microbiome Despite SIV Infection

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Moeller, Andrew H.; Peeters, Martine; Ayouba, Ahidjo; Ngole, Eitel Mpoudi; Esteban, Amadine; Hahn, Beatrice H.; Ochman, Howard

2015-01-01

Simian Immunodeficiency Viruses (SIVs) have been discovered in over 45 primate species; however, the pathogenic potential of most SIV strains remains unknown due to difficulties inherent in observing wild populations. Because those SIV infections that are pathogenic have been shown to induce changes in the host's gut microbiome, monitoring the microbiota present in fecal samples can provide a noninvasive means for studying the effects of SIV infection on the health of wild-living primates. Here, we examine the effects of SIVgor, a close relative of SIVcpz of chimpanzees and HIV-1 of humans, on the gut bacterial communities residing within wild gorillas, revealing that gorilla gut microbiomes are exceptionally robust to SIV infection. In contrast to the microbiomes of HIV-1 infected humans and SIVcpz-infected chimpanzees, SIVgor-infected gorilla microbiomes exhibit neither rises in the frequencies of opportunistic pathogens nor elevated rates of microbial turnover within individual hosts. Regardless of SIV infection status, gorilla microbiomes assort into enterotypes, one of which is compositionally analogous to those identified in humans and chimpanzees. The other gorilla enterotype appears specialized for a leaf-based diet and is enriched in environmentally derived bacterial genera. We hypothesize that the acquisition of this gorilla-specific enterotype was enabled by lowered immune-system control over the composition of the microbiome. Our results indicate differences between the pathology of SIVgor and SIVcpz/HIV-1 infections, demonstrating the utility of investigating host microbial ecology as a means for studying disease in wild primates of high conservation priority. PMID:25545295

Human-Rhesus Monkey conflict at Rampur Village under Monohardi Upazila in Narsingdi District of Bangladesh

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M.F. Ahsan

2014-06-01

Full Text Available Human-Rhesus monkey conflicts were recorded at Rampur Village under Khidirpur Union Parishad of Monohardi upazila under Narsingdi District in Bangladesh from April to September 2012. There were three groups of Rhesus monkeys living in the area. The focal study group comprised 26 individuals (4 adult males, 6 adult females, 10 juveniles and 6 infants. The monkeys consumed parts of 10 plant species. From the questionnaire survey, it was found that the greatest damage caused by monkeys was on betel leaf vines and the least damage on vegetables. Eighty percent respondents opted to conserve the monkeys and 20% opined status quo. Some restricted areas (especially khas lands may be identified and planted with some fruit trees for survival of monkeys and for reducing conflicts with humans.

Soluble rhesus lymphocryptovirus gp350 protects against infection and reduces viral loads in animals that become infected with virus after challenge.

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Junji Sashihara

2011-10-01

Full Text Available Epstein-Barr virus (EBV is a human lymphocryptovirus that is associated with several malignancies. Elevated EBV DNA in the blood is observed in transplant recipients prior to, and at the time of post-transplant lymphoproliferative disease; thus, a vaccine that either prevents EBV infection or lowers the viral load might reduce certain EBV malignancies. Two major approaches have been suggested for an EBV vaccine- immunization with either EBV glycoprotein 350 (gp350 or EBV latency proteins (e.g. EBV nuclear antigens [EBNAs]. No comparative trials, however, have been performed. Rhesus lymphocryptovirus (LCV encodes a homolog for each gene in EBV and infection of monkeys reproduces the clinical, immunologic, and virologic features of both acute and latent EBV infection. We vaccinated rhesus monkeys at 0, 4 and 12 weeks with (a soluble rhesus LCV gp350, (b virus-like replicon particles (VRPs expressing rhesus LCV gp350, (c VRPs expressing rhesus LCV gp350, EBNA-3A, and EBNA-3B, or (d PBS. Animals vaccinated with soluble gp350 produced higher levels of antibody to the glycoprotein than those vaccinated with VRPs expressing gp350. Animals vaccinated with VRPs expressing EBNA-3A and EBNA-3B developed LCV-specific CD4 and CD8 T cell immunity to these proteins, while VRPs expressing gp350 did not induce detectable T cell immunity to gp350. After challenge with rhesus LCV, animals vaccinated with soluble rhesus LCV gp350 had the best level of protection against infection based on seroconversion, viral DNA, and viral RNA in the blood after challenge. Surprisingly, animals vaccinated with gp350 that became infected had the lowest LCV DNA loads in the blood at 23 months after challenge. These studies indicate that gp350 is critical for both protection against infection with rhesus LCV and for reducing the viral load in animals that become infected after challenge. Our results suggest that additional trials with soluble EBV gp350 alone, or in combination with

Induced Neurocysticercosis in Rhesus Monkeys (Macaca mulatta Produces Clinical Signs and Lesions Similar to Natural Disease in Man

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N. Chowdhury

2014-01-01

Full Text Available Neurocysticercosis is a serious endemic zoonosis resulting in increased cases of seizure and epilepsy in humans. The genesis of clinical manifestations of the disease through experimental animal models is poorly exploited. The monkeys may prove useful for the purpose due to their behavior and cognitive responses mimicking man. In this study, neurocysticercosis was induced in two rhesus monkeys each with 12,000 and 6,000 eggs, whereas three monkeys were given placebo. The monkeys given higher dose developed hyperexcitability, epileptic seizures, muscular tremors, digital cramps at 10 DPI, and finally paralysis of limbs, followed by death on 67 DPI, whereas the monkeys given lower dose showed delayed and milder clinical signs. On necropsy, all the infected monkeys showed numerous cysticerci in the brain. Histopathologically, heavily infected monkeys revealed liquefactive necrosis and formation of irregular cystic cavities lined by atrophied parenchymal septa with remnants of neuropil of the cerebrum. In contrast, the monkeys infected with lower dose showed formation of typical foreign body granulomas characterized by central liquefaction surrounded by chronic inflammatory response. It was concluded that the inflammatory and immune response exerted by the host against cysticerci, in turn, led to histopathological lesions and the resultant clinical signs thereof.

Distinct phenotype, longitudinal changes of numbers and cell-associated virus in blood dendritic cells in SIV-infected CD8-lymphocyte depleted macaques.

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Caroline Soulas

Full Text Available Loss of circulating CD123+ plasmacytoid dendritic cells (pDCs during HIV infection is well established. However, changes of myeloid DCs (mDCs are ambiguous since they are studied as a homogeneous CD11c+ population despite phenotypic and functional heterogeneity. Heterogeneity of CD11c+ mDCs in primates is poorly described in HIV and SIV infection. Using multiparametric flow cytometry, we monitored longitudinally cell number and cell-associated virus of CD123+ pDCs and non-overlapping subsets of CD1c+ and CD16+ mDCs in SIV-infected CD8-depleted rhesus macaques. The numbers of all three DC subsets were significantly decreased by 8 days post-infection. Whereas CD123+ pDCs were persistently depleted, numbers of CD1c+ and CD16+ mDCs rebounded. Numbers of CD1c+ mDCs significantly increased by 3 weeks post-infection while numbers of CD16+ mDCs remained closer to pre-infection levels. We found similar changes in the numbers of all three DC subsets in CD8 depleted animals as we found in animals that were SIV infected animals that were not CD8 lymphocyte depleted. CD16+ mDCs and CD123+ pDCs but not CD1c+ mDCs were significantly decreased terminally with AIDS. All DC subsets harbored SIV RNA as early as 8 days and then throughout infection. However, SIV DNA was only detected in CD123+ pDCs and only at 40 days post-infection consistent with SIV RNA, at least in mDCs, being surface-bound. Altogether our data demonstrate that SIV infection differently affects CD1c+ and CD16+ mDCs where CD16+ but not CD1c+ mDCs are depleted and might be differentially regulated in terminal AIDS. Finally, our data underline the importance of studying CD1c+ and CD16+ mDCs as discrete populations, and not as total CD11c+ mDCs.

Nature of the Refractive Errors in Rhesus Monkeys (Macaca mulatta) with Experimentally Induced Ametropias

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Qiao-Grider, Ying; Hung, Li-Fang; Kee, Chea-su; Ramamirtham, Ramkumar; Smith, Earl L.

2010-01-01

We analyzed the contribution of individual ocular components to vision-induced ametropias in 210 rhesus monkeys. The primary contribution to refractive-error development came from vitreous chamber depth; a minor contribution from corneal power was also detected. However, there was no systematic relationship between refractive error and anterior chamber depth or between refractive error and any crystalline lens parameter. Our results are in good agreement with previous studies in humans, suggesting that the refractive errors commonly observed in humans are created by vision-dependent mechanisms that are similar to those operating in monkeys. This concordance emphasizes the applicability of rhesus monkeys in refractive-error studies. PMID:20600237

Revisiting a quarter of a century of simian immunodeficiency virus (SIV-associated cardiovascular diseases at the German Primate Center

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M. Mietsch

2017-06-01

Full Text Available Human immunodeficiency virus (HIV comorbidities have become clinically more important due to antiretroviral therapy. Although therapy increases life expectancy, it does not completely suppress immune activation and its associated complications. The simian immunodeficiency virus (SIV-infected rhesus macaque (Macaca mulatta represents a valuable model for the investigation of SIV-associated diseases. Although cardiovascular (CV changes are common in HIV-infected patients, there are only a few reports on the incidence of CV findings in SIV-infected animals. In addition, potential associations between pathohistological findings and hematological parameters are still unclear. We therefore conducted a retrospective analysis of 195 SIV-infected rhesus macaques that were euthanized with AIDS-related symptoms at the German Primate Center, Goettingen, over a 25-year period. Pathological findings were correlated with hematological data. The main findings included myocarditis (12.8 %, endocarditis (9.7 %, and arteriopathy (10.3 % in various organs. Thrombocytopenia occurred more frequently in macaques with endocarditis or arteriopathy than in macaques without CV disease (80 % in animals with endocarditis, 60 % in animals with arteriopathy, p < 0. 0001 and p = 0. 0016, respectively. Further investigations of the interaction between coagulation markers, proinflammatory cytokines, and biomarkers associated with endothelial dysfunction (e.g., D-dimers and histological data (vascular wall structure may unravel the mechanisms underlying HIV/SIV-associated CV comorbidities.

Rhesus monkeys see who they hear: spontaneous cross-modal memory for familiar conspecifics.

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Ikuma Adachi

Full Text Available Rhesus monkeys gather much of their knowledge of the social world through visual input and may preferentially represent this knowledge in the visual modality. Recognition of familiar faces is clearly advantageous, and the flexibility and utility of primate social memory would be greatly enhanced if visual memories could be accessed cross-modally either by visual or auditory stimulation. Such cross-modal access to visual memory would facilitate flexible retrieval of the knowledge necessary for adaptive social behavior. We tested whether rhesus monkeys have cross-modal access to visual memory for familiar conspecifics using a delayed matching-to-sample procedure. Monkeys learned visual matching of video clips of familiar individuals to photographs of those individuals, and generalized performance to novel videos. In crossmodal probe trials, coo-calls were played during the memory interval. The calls were either from the monkey just seen in the sample video clip or from a different familiar monkey. Even though the monkeys were trained exclusively in visual matching, the calls influenced choice by causing an increase in the proportion of errors to the picture of the monkey whose voice was heard on incongruent trials. This result demonstrates spontaneous cross-modal recognition. It also shows that viewing videos of familiar monkeys activates naturally formed memories of real monkeys, validating the use of video stimuli in studies of social cognition in monkeys.

Evaluation of polymorphonuclear leukocyte chemotaxis of adult and neonatal rhesus monkeys using 51-chromium labeling method

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Kinoshita, Yo; Masuda, Kiyokazu; Kobayashi, Yohnosuke

1987-01-01

Chemotaxis of polymorphonuclear leukocytes (PMN) from heparinized venous blood of 8 adult rhesus monkeys (Macaca Mulatta) and 13 rhesus monkey neonates within 48 hours of birth were evaluated by using 51-chromium labeling method. PMNs were prepared by Ficoll-Hypaque gradient and dextran sedimentation procedures and the final 51-chromium uptake was 3.21 ± 1.27 % to original count. PMN chemotaxis was succeeded by using two different chemotaxis filters (Nuclepore filter on top of Millipore filter) with incubation at 37 deg C for 90 min. The mean value of target: non target ratio (CPM in lower filter with chemoattractant/CPM in lower filter without chemoattractant) of 3.56 ± 2.49 from neonates showed no significant difference from that of 4.44 ± 1.24 from adults. Only about 30 % of neonates showed an impaired chemotaxis, but others showed similar chemotactic activity as adults. The results show that the 51-chromium labeling method is useful to assess neutrophil functions in rhesus monkey species and suggest that host defense mechanism of the rhesus monkey may differ from that of human in neonatal period. (author)

Total lymphoid irradiation in rhesus monkeys

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Vriesendorp, H.M.; Maat, B.; Hogeweg, B.

Total lymphoid irradiation (TLI) consists of three contiguous fields, a mantle, an inverted Y and a spleen field. TLI induces a state of immunosuppression in patients with Hodgkin disease or in small rodents. Infusion of allogeneic bone marrow cells into mice after TLI led to the development split haemopoietic chimerism and indefinite survival of skin grafts from the bone marrow donor. A protocol for TLI was developed for rhesus monkeys to attempt to verify these interesting observations in a pre-clinical animal model. (Auth.)

Evaluation of an intragastric challenge model for Shigella dysenteriae 1 in rhesus monkeys (Macaca mulatta) for the pre-clinical assessment of Shigella vaccine formulations.

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Islam, Dilara; Ruamsap, Nattaya; Khantapura, Patchariya; Aksomboon, Ajchara; Srijan, Apichai; Wongstitwilairoong, Boonchai; Bodhidatta, Ladaporn; Gettayacamin, Montip; Venkatesan, Malabi M; Mason, Carl J

2014-06-01

Shigellosis is a worldwide disease, characterized by abdominal pain, fever, vomiting, and the passage of blood- and mucus-streaked stools. Rhesus monkeys and other primates are the only animals that are naturally susceptible to shigellosis. A suitable animal model is required for the pre-clinical evaluation of vaccines candidates. In this study, the minimal dose of Shigella dysenteriae1 1617 strain required to produce dysentery in four of five (80% attack rate) monkeys using an escalating dose range for three groups [2 × 10(8) , 2 × 10(9) and 2 × 10(10) colony forming unit (CFU)] was determined. In addition, the monkeys were re-infected. The identified optimal challenge dose was 2 × 10(9) CFU; this dose elicited 60% protection in monkeys when they were re-challenged with a one log higher dose (2 × 10(10) CFU). The challenge dose, 2 × 10(10) CFU, produced severe dysentery in all monkeys, with one monkey dying within 24 h, elicited 100% protection when re-challenged with the same dose. All monkeys exhibited immune responses. This study concludes that the rhesus monkey model closely mimics the disease and immune response seen in humans and is a suitable animal model for the pre-clinical evaluation of Shigella vaccine candidates. Prior infection with the 1617 strain can protect monkeys against subsequent re-challenges with homologous strains. © 2013 The Authors. APMIS published by John Wiley & Sons Ltd.

Kinetics of liver macrophages (Kupffer cells) in SIV-infected macaques

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Ahsan, Muhammad H.; Gill, Amy F.; Alvarez, Xavier; Lackner, Andrew A.; Veazey, Ronald S.

2013-01-01

Since the liver drains antigens from the intestinal tract, and since the intestinal tract is a major site of viral replication, we examined the dynamics of liver macrophages (Kupffer cells) throughout SIV infection. Absolute numbers of Kupffer cells increased in the livers in acute infection, and in animals with AIDS. Significantly higher percentages of proliferating (BrdU+) Kupffer cells were detected in acute infection and in AIDS with similar trends in blood monocytes. Significantly higher percentages of apoptotic (AC3+) Kupffer cells were also found in acute and AIDS stages. However, productively infected cells were not detected in liver of 41/42 animals examined, despite abundant infected cells in gut and lymph nodes of all animals. Increased rates of Kupffer cell proliferation resulting in an increase in Kupffer cells without productive infection indicate SIV infection affects Kupffer cells, but the liver does not appear to be a major site of productive viral replication. - Highlights: • Kupffer cells increase in the liver of SIV-infected macaques. • Increased proliferation and apoptosis of Kupffer cells occurs in SIV infection. • Productively infected cells are rarely detected in the liver. • The liver is not a major site for SIV replication

Increased cellular immune responses and CD4+ T-cell proliferation correlate with reduced plasma viral load in SIV challenged recombinant simian varicella virus - simian immunodeficiency virus (rSVV-SIV vaccinated rhesus macaques

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Pahar Bapi

2012-08-01

Full Text Available Abstract Background An effective AIDS vaccine remains one of the highest priorities in HIV-research. Our recent study showed that vaccination of rhesus macaques with recombinant simian varicella virus (rSVV vector – simian immunodeficiency virus (SIV envelope and gag genes, induced neutralizing antibodies and cellular immune responses to SIV and also significantly reduced plasma viral loads following intravenous pathogenic challenge with SIVMAC251/CX1. Findings The purpose of this study was to define cellular immunological correlates of protection in rSVV-SIV vaccinated and SIV challenged animals. Immunofluorescent staining and multifunctional assessment of SIV-specific T-cell responses were evaluated in both Experimental and Control vaccinated animal groups. Significant increases in the proliferating CD4+ T-cell population and polyfunctional T-cell responses were observed in all Experimental-vaccinated animals compared with the Control-vaccinated animals. Conclusions Increased CD4+ T-cell proliferation was significantly and inversely correlated with plasma viral load. Increased SIV-specific polyfunctional cytokine responses and increased proliferation of CD4+ T-cell may be crucial to control plasma viral loads in vaccinated and SIVMAC251/CX1 challenged macaques.

Serological reactions in Rhesus monkeys inoculated with the 17D strain of yellow fever virus.

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GROOT, H

1962-01-01

Haemagglutination-inhibition tests, which depend on the appearance of haemagglutination-inhibiting antibodies in the serum in virus infections, are in common use in the study of arthropod-borne diseases. This paper contains the results of an investigation into the appearance and pattern of haemagglutination-inhibiting antibodies in the serum of rhesus monkeys inoculated intracerebrally with the 17D strain of yellow fever virus during the testing of seed lots of yellow fever vaccine. These antibodies appeared on the tenth day after inoculation, and were still demonstrable four years later. In all of the eight monkeys tested complement-fixing and neutralizing antibodies against yellow fever antigens also developed, and in six out of the eight heterologous antigens developed.

Perceived control in rhesus monkeys (Macaca mulatta) - Enhanced video-task performance

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Washburn, David A.; Hopkins, William D.; Rumbaugh, Duane M.

1991-01-01

This investigation was designed to determine whether perceived control effects found in humans extend to rhesus monkeys (Macaca mulatta) tested in a video-task format, using a computer-generated menu program, SELECT. Choosing one of the options in SELECT resulted in presentation of five trials of a corresponding task and subsequent return to the menu. In Experiments 1-3, the animals exhibited stable, meaningful response patterns in this task (i.e., they made choices). In Experiment 4, performance on tasks that were selected by the animals significantly exceeded performance on identical tasks when assigned by the experimenter under comparable conditions (e.g., time of day, order, variety). The reliable and significant advantage for performance on selected tasks, typically found in humans, suggests that rhesus monkeys were able to perceive the availability of choices.

Characterization of the Sweet Taste Receptor Tas1r2 from an Old World Monkey Species Rhesus Monkey and Species-Dependent Activation of the Monomeric Receptor by an Intense Sweetener Perillartine.

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Chenggu Cai

Full Text Available Sweet state is a basic physiological sensation of humans and other mammals which is mediated by the broadly acting sweet taste receptor-the heterodimer of Tas1r2 (taste receptor type 1 member 2 and Tas1r3 (taste receptor type 1 member 3. Various sweeteners interact with either Tas1r2 or Tas1r3 and then activate the receptor. In this study, we cloned, expressed and functionally characterized the taste receptor Tas1r2 from a species of Old World monkeys, the rhesus monkey. Paired with the human TAS1R3, it was shown that the rhesus monkey Tas1r2 could respond to natural sugars, amino acids and their derivates. Furthermore, similar to human TAS1R2, rhesus monkey Tas1r2 could respond to artificial sweeteners and sweet-tasting proteins. However, the responses induced by rhesus monkey Tas1r2 could not be inhibited by the sweet inhibitor amiloride. Moreover, we found a species-dependent activation of the Tas1r2 monomeric receptors of human, rhesus monkey and squirrel monkey but not mouse by an intense sweetener perillartine. Molecular modeling and sequence analysis indicate that the receptor has the conserved domains and ligand-specific interactive residues, which have been identified in the characterized sweet taste receptors up to now. This is the first report of the functional characterization of sweet taste receptors from an Old World monkey species.

Characterization of the Sweet Taste Receptor Tas1r2 from an Old World Monkey Species Rhesus Monkey and Species-Dependent Activation of the Monomeric Receptor by an Intense Sweetener Perillartine.

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Cai, Chenggu; Jiang, Hua; Li, Lei; Liu, Tianming; Song, Xuejie; Liu, Bo

2016-01-01

Sweet state is a basic physiological sensation of humans and other mammals which is mediated by the broadly acting sweet taste receptor-the heterodimer of Tas1r2 (taste receptor type 1 member 2) and Tas1r3 (taste receptor type 1 member 3). Various sweeteners interact with either Tas1r2 or Tas1r3 and then activate the receptor. In this study, we cloned, expressed and functionally characterized the taste receptor Tas1r2 from a species of Old World monkeys, the rhesus monkey. Paired with the human TAS1R3, it was shown that the rhesus monkey Tas1r2 could respond to natural sugars, amino acids and their derivates. Furthermore, similar to human TAS1R2, rhesus monkey Tas1r2 could respond to artificial sweeteners and sweet-tasting proteins. However, the responses induced by rhesus monkey Tas1r2 could not be inhibited by the sweet inhibitor amiloride. Moreover, we found a species-dependent activation of the Tas1r2 monomeric receptors of human, rhesus monkey and squirrel monkey but not mouse by an intense sweetener perillartine. Molecular modeling and sequence analysis indicate that the receptor has the conserved domains and ligand-specific interactive residues, which have been identified in the characterized sweet taste receptors up to now. This is the first report of the functional characterization of sweet taste receptors from an Old World monkey species.

Estudo comparativo das inclusões do alastrim e da vacina no macaco (Macacus rhesus A comparison of the inclusion bodies of alastrim and vaccinia in the monkey (Macacus rhesus

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C. Magarinos Torres

1934-02-01

. While 12 rhesus monkeys injected intravenously with seven strains of alastrim virus developed regularly an experimental infection and finally recovered and remained well, the intravenous injection of vaccine virus was followed by death in two from four rhesus monkeys injected. 2. Slight but definite and regular differences were noticed between alastrim and vaccine bodies after fixation in Helly's fluid, embedding in paraffin and staining with alum hematoxylin and eosin. They are related to the number of inclusions within the cell and to their staining. 3. - In each cell of the epidermis of Macacus rhesus there is usually a single alastrim body when late stages are considered, and quite a few (2-4 when early stages are observed. Alastrim bodies stain a deep blue to grayish-blue. Nevertheless, in necrotic epidermal cells or in cells provided with a few small inclusions they sometimes present a pink staining. 4. - Vaccine bodies in late stages of development are numerous in each epidermal cell of the rhesus monkey and present regularly a characteristic polychromatophilia.

Phenotypic and Functional Characterization of Monoclonal Antibodies with Specificity for Rhesus Macaque CD200, CD200R and Mincle.

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Siddappa N Byrareddy

Full Text Available Lectin-like molecules and their receptors are cell surface molecules that have been shown to play a role in either facilitating infection or serving as transporters of HIV/SIV in vivo. The role of these lectin-like molecules in the pathogenesis of HIV/SIV infection continues to be defined. In efforts to gain further insight on the potential role of these lectin-like molecules, our laboratory generated monoclonal antibodies (mAb against the human analogs of rhesus macaque CD200, CD200R and Mincle, since the rhesus macaques are accepted as the most reliable animal model to study human HIV infection. The characterization of the cell lineages from the blood and various tissues of rhesus macaques that express these lectin-like molecules are described herein. Among the mononuclear cells, the cells of the myeloid lineage of rhesus macaques are the predominant cell lineages that express readily detectable levels of CD200, CD200R and Mincle that is similar to the expression of Siglec-1 and Siglec-3 reported by our laboratory earlier. Subset analysis revealed that a higher frequency of the CD14+/CD16- subset from normal rhesus macaques express CD200, CD200R and Mincle. Differences in the frequencies and density of expression of these molecules by the gated population of CD14+ cells from various tissues are noted with PBMC and bone marrow expressing the highest and the mononuclear cells isolated from the colon and ileum expressing the lowest levels. While a significant frequency of pDCs and mDCs express Siglec-1/Siglec-3, a much lower frequency expresses CD200, CD200R and Mincle in PBMCs from rhesus macaques. The mAb against CD200 and CD200R but not Mincle appear to inhibit the infection of macrophage tropic SIV/SHIV in vitro. We conclude that these mAbs may have potential to be used as adjunctive therapeutic agents to control/inhibit SIV/HIV infection.

Programed death-1/programed death-ligand 1 expression in lymph nodes of HIV infected patients: results of a pilot safety study in rhesus macaques using anti–programed death-ligand 1 (Avelumab)

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Gill, Amanda L.; Green, Samantha A.; Abdullah, Shahed; Le Saout, Cecile; Pittaluga, Stefania; Chen, Hui; Turnier, Refika; Lifson, Jeffrey; Godin, Steven; Qin, Jing; Sneller, Michael C.; Cuillerot, Jean-Marie; Sabzevari, Helen; Lane, H. Clifford; Catalfamo, Marta

2016-01-01

Objective: The programed death-1 (PD1)/programed death-ligand 1 (PD-L1) pathway plays a critical role in balancing immunity and host immunopathology. During chronic HIV/SIV infection, there is persistent immune activation accompanied by accumulation of virus-specific cells with terminally differentiated phenotypes and expression of regulatory receptors such as PD1. These observations led us to hypothesize that the PD1/PD-L1 pathway contributes to the functional dysregulation and ineffective viral control, and its blockade may be a potential immunotherapeutic target. Methods: Lymph node biopsies from HIV-infected patients (n = 23) were studied for expression of PD1 and PD-L1. In addition, we assessed the safety and biological activity of a human anti-PD-L1 antibody (Avelumab) in chronically SIV-infected rhesus macaques. Results: PD-L1 expression was observed in cells with myloid/macrophage morphology in HIV-infected lymph nodes. Administration of anti-PD-L1 was well tolerated, and no changes in body weights, hematologic, or chemistry parameters were observed during the study. Blockade of PD-L1 led to a trend of transient viral control after discontinuation of treatment. Conclusion: Administration of anti-PD-L1 in chronic SIV-infected rhesus macaques was well tolerated. Overall, these data warrant further investigation to assess the efficacy of anti-PD-L1 treatment on viral control in chronic SIV infection as a prelude to such therapy in humans. PMID:27490642

Programed death-1/programed death-ligand 1 expression in lymph nodes of HIV infected patients: results of a pilot safety study in rhesus macaques using anti-programed death-ligand 1 (Avelumab).

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Gill, Amanda L; Green, Samantha A; Abdullah, Shahed; Le Saout, Cecile; Pittaluga, Stefania; Chen, Hui; Turnier, Refika; Lifson, Jeffrey; Godin, Steven; Qin, Jing; Sneller, Michael C; Cuillerot, Jean-Marie; Sabzevari, Helen; Lane, H Clifford; Catalfamo, Marta

2016-10-23

The programed death-1 (PD1)/programed death-ligand 1 (PD-L1) pathway plays a critical role in balancing immunity and host immunopathology. During chronic HIV/SIV infection, there is persistent immune activation accompanied by accumulation of virus-specific cells with terminally differentiated phenotypes and expression of regulatory receptors such as PD1. These observations led us to hypothesize that the PD1/PD-L1 pathway contributes to the functional dysregulation and ineffective viral control, and its blockade may be a potential immunotherapeutic target. Lymph node biopsies from HIV-infected patients (n = 23) were studied for expression of PD1 and PD-L1. In addition, we assessed the safety and biological activity of a human anti-PD-L1 antibody (Avelumab) in chronically SIV-infected rhesus macaques. PD-L1 expression was observed in cells with myloid/macrophage morphology in HIV-infected lymph nodes. Administration of anti-PD-L1 was well tolerated, and no changes in body weights, hematologic, or chemistry parameters were observed during the study. Blockade of PD-L1 led to a trend of transient viral control after discontinuation of treatment. Administration of anti-PD-L1 in chronic SIV-infected rhesus macaques was well tolerated. Overall, these data warrant further investigation to assess the efficacy of anti-PD-L1 treatment on viral control in chronic SIV infection as a prelude to such therapy in humans.

Viral CTL escape mutants are generated in lymph nodes and subsequently become fixed in plasma and rectal mucosa during acute SIV infection of macaques.

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Thomas H Vanderford

2011-05-01

Full Text Available SIV(mac239 infection of rhesus macaques (RMs results in AIDS despite the generation of a strong antiviral cytotoxic T lymphocyte (CTL response, possibly due to the emergence of viral escape mutants that prevent recognition of infected cells by CTLs. To determine the anatomic origin of these SIV mutants, we longitudinally assessed the presence of CTL escape variants in two MamuA*01-restricted immunodominant epitopes (Tat-SL8 and Gag-CM9 in the plasma, PBMCs, lymph nodes (LN, and rectal biopsies (RB of fifteen SIV(mac239-infected RMs. As expected, Gag-CM9 did not exhibit signs of escape before day 84 post infection. In contrast, Tat-SL8 escape mutants were apparent in all tissues by day 14 post infection. Interestingly LNs and plasma exhibited the highest level of escape at day 14 and day 28 post infection, respectively, with the rate of escape in the RB remaining lower throughout the acute infection. The possibility that CTL escape occurs in LNs before RBs is confirmed by the observation that the specific mutants found at high frequency in LNs at day 14 post infection became dominant at day 28 post infection in plasma, PBMC, and RB. Finally, the frequency of escape mutants in plasma at day 28 post infection correlated strongly with the level Tat-SL8-specific CD8 T cells in the LN and PBMC at day 14 post infection. These results indicate that LNs represent the primary source of CTL escape mutants during the acute phase of SIV(mac239 infection, suggesting that LNs are the main anatomic sites of virus replication and/or the tissues in which CTL pressure is most effective in selecting SIV escape variants.

Tolerance to Chronic Delta-9-Tetrahydrocannabinol (Δ9-THC) in Rhesus Macaques Infected With Simian Immunodeficiency Virus

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Winsauer, Peter J.; Molina, Patricia E.; Amedee, Angela M.; Filipeanu, Catalin M.; McGoey, Robin R.; Troxclair, Dana A.; Walker, Edith M.; Birke, Leslie L.; Stouwe, Curtis Vande; Howard, Jessica M.; Leonard, Stuart T.; Moerschbaecher, Joseph M.; Lewis, Peter B.

2011-01-01

Although Δ9-THC has been approved to treat anorexia and weight loss associated with AIDS, it may also reduce well-being by disrupting complex behavioral processes or enhancing HIV replication. To investigate these possibilities, four groups of male rhesus macaques were trained to respond under an operant acquisition and performance procedure, and administered vehicle or Δ9-THC before and after inoculation with simian immunodeficiency virus(SIVmac251, 100 TCID50/ml, i.v.). Prior to chronic Δ9-THC and SIV inoculation, 0.032– 0.32 mg/kg of Δ9-THC produced dose-dependent rate-decreasing effects and small, sporadic error-increasing effects in the acquisition and performance components in each subject. Following 28 days of chronic Δ9-THC (0.32 mg/kg, i.m.) or vehicle twice daily, delta-9-THC-treated subjects developed tolerance to the rate-decreasing effects, and this tolerance was maintained during the initial 7–12 months irrespective of SIV infection (i.e., +THC/−SIV, +THC/+SIV). Full necropsy was performed on all SIV subjects an average of 329 days post-SIV inoculation, with postmortem histopathology suggestive of a reduced frequency of CNS pathology as well as opportunistic infections in delta-9-THC-treated subjects. Chronic Δ9-THC also significantly reduced CB-1 and CB-2 receptor levels in the hippocampus, attenuated the expression of a proinflammatory cytokine (MCP-1), and did not increase viral load in plasma, cerebrospinal fluid, or brain tissue compared to vehicle-treated subjects with SIV. Together, these data indicate that chronic Δ9-THC produces tolerance to its behaviorally disruptive effects on complex tasks while not adversely affecting viral load or other markers of disease progression during the early stages of infection. PMID:21463073

Transplantation of adult monkey neural stem cells into a contusion spinal cord injury model in rhesus macaque monkeys

DEFF Research Database (Denmark)

Nemati, Shiva Nemati; Jabbari, Reza; Hajinasrollah, Mostafa

2014-01-01

, therefore, to explore the efficacy of adult monkey NSC (mNSC) in a primate SCI model. MATERIALS AND METHODS: In this experimental study, isolated mNSCs were analyzed by flow cytometry, immunocytochemistry, and RT-PCR. Next, BrdU-labeled cells were transplanted into a SCI model. The SCI animal model...... on Tarlov's scale and our established behavioral tests for monkeys. CONCLUSION: Our findings have indicated that mNSCs can facilitate recovery in contusion SCI models in rhesus macaque monkeys. Additional studies are necessary to determine the im- provement mechanisms after cell transplantation....

Relationships between luminance and visual acuity in the rhesus monkey

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Cavonius, C. R.; Robbins, D. O.

1973-01-01

1. The ability of rhesus monkeys to detect the gap in Landolt ring test-objects that were presented against background luminances between 5 × 10-5 cd/m2 and 5 × 103 cd/m2 was compared with similar human data. 2. At high luminance-levels the acuity of human observers is slightly better than that of rhesus, but rhesus have better acuity at scotopic luminance-levels. Both species have distinct photopic and scotopic acuity functions that cross at 6 × 10-3 cd/m2. 3. The threshold for light detection is estimated to be the same for both species when specified in quanta incident on the retina. 4. It is concluded that the receptor and neural mechanisms that mediate visual-acuity function similarly in rhesus and man, and that the differences in acuity that were measured in the two species may be attributed to optical rather than to physiological factors. PMID:4199366

Investigations of rhesus monkey video-task performance: evidence for enrichment

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Washburn, D. A.; Rumbaugh, D. M.

1992-01-01

We have developed the Language Research Center's Computerized Test System (LRC-CTS) for psychological research. Basically, the LRC-CTS is a battery of software tasks--computerized versions of many of the classic testing paradigms of cognitive and comparative psychology--and the hardware required to administer them. An XT- or 386-compatible computer is connected to a color monitor, onto which computer-generated stimuli are presented. Sound feedback is delivered through an external speaker/amplifier, and a joystick is used as an input device. The animals reach through the mesh of their home cages to manipulate the joystick, which causes isomorphic movements of a cursor on the screen thereby allowing animals to respond according to the varied demands of the tasks. Correct responses are rewarded with a fruit-flavored chow pellet. Using this technology, we have trained and tested rhesus monkeys, a variety of apes, human adults, and normally developing or mentally retarded human children. Other labs using the LRC-CTS are beginning to report encouraging results with other monkey species as well. From this research, a number of interesting and important psychological findings have resulted. In the present paper, however, evidence will be reviewed which suggests that the LRC-CTS is an effective means of providing environmental enrichment to singly housed rhesus monkeys.

Simian Immunodeficiency Virus (SIV-Specific Chimeric Antigen Receptor-T Cells Engineered to Target B Cell Follicles and Suppress SIV Replication

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Kumudhini Preethi Haran

2018-03-01

Full Text Available There is a need to develop improved methods to treat and potentially cure HIV infection. During chronic HIV infection, replication is concentrated within T follicular helper cells (Tfh located within B cell follicles, where low levels of virus-specific CTL permit ongoing viral replication. We previously showed that elevated levels of simian immunodeficiency virus (SIV-specific CTL in B cell follicles are linked to both decreased levels of viral replication in follicles and decreased plasma viral loads. These findings provide the rationale to develop a strategy for targeting follicular viral-producing (Tfh cells using antiviral chimeric antigen receptor (CAR T cells co-expressing the follicular homing chemokine receptor CXCR5. We hypothesize that antiviral CAR/CXCR5-expressing T cells, when infused into an SIV-infected animal or an HIV-infected individual, will home to B cell follicles, suppress viral replication, and lead to long-term durable remission of SIV and HIV. To begin to test this hypothesis, we engineered gammaretroviral transduction vectors for co-expression of a bispecific anti-SIV CAR and rhesus macaque CXCR5. Viral suppression by CAR/CXCR5-transduced T cells was measured in vitro, and CXCR5-mediated migration was evaluated using both an in vitro transwell migration assay, as well as a novel ex vivo tissue migration assay. The functionality of the CAR/CXCR5 T cells was demonstrated through their potent suppression of SIVmac239 and SIVE660 replication in in vitro and migration to the ligand CXCL13 in vitro, and concentration in B cell follicles in tissues ex vivo. These novel antiviral immunotherapy products have the potential to provide long-term durable remission (functional cure of HIV and SIV infections.

Mucosal B Cells Are Associated with Delayed SIV Acquisition in Vaccinated Female but Not Male Rhesus Macaques Following SIVmac251 Rectal Challenge.

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Iskra Tuero

2015-08-01

Full Text Available Many viral infections, including HIV, exhibit sex-based pathogenic differences. However, few studies have examined vaccine-related sex differences. We compared immunogenicity and protective efficacy of monomeric SIV gp120 with oligomeric SIV gp140 in a pre-clinical rhesus macaque study and explored a subsequent sex bias in vaccine outcome. Each immunization group (16 females, 8 males was primed twice mucosally with replication-competent Ad-recombinants encoding SIVsmH4env/rev, SIV239gag and SIV239nefΔ1-13 and boosted twice intramuscularly with SIVmac239 monomeric gp120 or oligomeric gp140 in MF59 adjuvant. Controls (7 females, 5 males received empty Ad and MF59. Up to 9 weekly intrarectal challenges with low-dose SIVmac251 were administered until macaques became infected. We assessed vaccine-induced binding, neutralizing, and non-neutralizing antibodies, Env-specific memory B cells and plasmablasts/plasma cells (PB/PC in bone marrow and rectal tissue, mucosal Env-specific antibodies, and Env-specific T-cells. Post-challenge, only one macaque (gp140-immunized remained uninfected. However, SIV acquisition was significantly delayed in vaccinated females but not males, correlated with Env-specific IgA in rectal secretions, rectal Env-specific memory B cells, and PC in rectal tissue. These results extend previous correlations of mucosal antibodies and memory B cells with protective efficacy. The gp140 regimen was more immunogenic, stimulating elevated gp140 and cyclic V2 binding antibodies, ADCC and ADCP activities, bone marrow Env-specific PB/PC, and rectal gp140-specific IgG. However, immunization with gp120, the form of envelope immunogen used in RV144, the only vaccine trial to show some efficacy, provided more significant acquisition delay. Further over 40 weeks of follow-up, no gp120 immunized macaques met euthanasia criteria in contrast to 7 gp140-immunized and 2 control animals. Although males had higher binding antibodies than females, ADCC

Mucosal B Cells Are Associated with Delayed SIV Acquisition in Vaccinated Female but Not Male Rhesus Macaques Following SIVmac251 Rectal Challenge.

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Tuero, Iskra; Mohanram, Venkatramanan; Musich, Thomas; Miller, Leia; Vargas-Inchaustegui, Diego A; Demberg, Thorsten; Venzon, David; Kalisz, Irene; Kalyanaraman, V S; Pal, Ranajit; Ferrari, Maria Grazia; LaBranche, Celia; Montefiori, David C; Rao, Mangala; Vaccari, Monica; Franchini, Genoveffa; Barnett, Susan W; Robert-Guroff, Marjorie

2015-08-01

Many viral infections, including HIV, exhibit sex-based pathogenic differences. However, few studies have examined vaccine-related sex differences. We compared immunogenicity and protective efficacy of monomeric SIV gp120 with oligomeric SIV gp140 in a pre-clinical rhesus macaque study and explored a subsequent sex bias in vaccine outcome. Each immunization group (16 females, 8 males) was primed twice mucosally with replication-competent Ad-recombinants encoding SIVsmH4env/rev, SIV239gag and SIV239nefΔ1-13 and boosted twice intramuscularly with SIVmac239 monomeric gp120 or oligomeric gp140 in MF59 adjuvant. Controls (7 females, 5 males) received empty Ad and MF59. Up to 9 weekly intrarectal challenges with low-dose SIVmac251 were administered until macaques became infected. We assessed vaccine-induced binding, neutralizing, and non-neutralizing antibodies, Env-specific memory B cells and plasmablasts/plasma cells (PB/PC) in bone marrow and rectal tissue, mucosal Env-specific antibodies, and Env-specific T-cells. Post-challenge, only one macaque (gp140-immunized) remained uninfected. However, SIV acquisition was significantly delayed in vaccinated females but not males, correlated with Env-specific IgA in rectal secretions, rectal Env-specific memory B cells, and PC in rectal tissue. These results extend previous correlations of mucosal antibodies and memory B cells with protective efficacy. The gp140 regimen was more immunogenic, stimulating elevated gp140 and cyclic V2 binding antibodies, ADCC and ADCP activities, bone marrow Env-specific PB/PC, and rectal gp140-specific IgG. However, immunization with gp120, the form of envelope immunogen used in RV144, the only vaccine trial to show some efficacy, provided more significant acquisition delay. Further over 40 weeks of follow-up, no gp120 immunized macaques met euthanasia criteria in contrast to 7 gp140-immunized and 2 control animals. Although males had higher binding antibodies than females, ADCC and ADCP

Transmission of naturally occurring lymphoma in macaque monkeys.

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Hunt, R D; Blake, B J; Chalifoux, L V; Sehgal, P K; King, N W; Letvin, N L

1983-01-01

Spontaneously occurring rhesus monkey lymphomas were transmitted into healthy rhesus monkeys by using tumor cell suspensions. The naturally arising tumors included an immunoblastic sarcoma and an undifferentiated lymphoma. Recipient animals developed undifferentiated lymphomas, poorly differentiated lymphomas, or parenchymal lymphoproliferative abnormalities suggestive of early lesions of lymphoma. Some of these animals developed such opportunistic infections as cytomegalovirus hepatitis and ...

Comparison of the chromosomal radiosensitivity of blood lymphocytes and stem-cell spermatogonia in the rhesus monkey and the mouse

International Nuclear Information System (INIS)

Buul, P.P.W. van; Richardson, J.F.; Boer, P. de; Zwanenburg, S.

1980-01-01

By experiments similar to those with the mouse we studied, in the rhesus monkey (Macaca mulatta), the induction by X-rays of reciprocal translocations in steam-cell spermatogonia and of dicentric chromosomes in blood lymphocytes. Human blood lymphocytes and rhesus monkey lymphocytes showed about equal sensitivity to dicentric induction. This equal radiosensitivity of somatic cells, however, provides no clue to the quantitative extrapolation to the human situation of the data obtained on translocation induction in stem-cell spermatogonia of the rhesus monkey. In our opinion, only direct observations on induced chromosomal aberrations in germ cells of higher primates and man can play a decisive role in estimating human genetic radiation risks arising from chromosomal aberrations. (orig./AJ)

Multi-dose Romidepsin Reactivates Replication Competent SIV in Post-antiretroviral Rhesus Macaque Controllers.

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Benjamin B Policicchio

2016-09-01

Full Text Available Viruses that persist despite seemingly effective antiretroviral treatment (ART and can reinitiate infection if treatment is stopped preclude definitive treatment of HIV-1 infected individuals, requiring lifelong ART. Among strategies proposed for targeting these viral reservoirs, the premise of the "shock and kill" strategy is to induce expression of latent proviruses [for example with histone deacetylase inhibitors (HDACis] resulting in elimination of the affected cells through viral cytolysis or immune clearance mechanisms. Yet, ex vivo studies reported that HDACis have variable efficacy for reactivating latent proviruses, and hinder immune functions. We developed a nonhuman primate model of post-treatment control of SIV through early and prolonged administration of ART and performed in vivo reactivation experiments in controller RMs, evaluating the ability of the HDACi romidepsin (RMD to reactivate SIV and the impact of RMD treatment on SIV-specific T cell responses. Ten RMs were IV-infected with a SIVsmmFTq transmitted-founder infectious molecular clone. Four RMs received conventional ART for >9 months, starting from 65 days post-infection. SIVsmmFTq plasma viremia was robustly controlled to <10 SIV RNA copies/mL with ART, without viral blips. At ART cessation, initial rebound viremia to ~106 copies/mL was followed by a decline to < 10 copies/mL, suggesting effective immune control. Three post-treatment controller RMs received three doses of RMD every 35-50 days, followed by in vivo experimental depletion of CD8+ cells using monoclonal antibody M-T807R1. RMD was well-tolerated and resulted in a rapid and massive surge in T cell activation, as well as significant virus rebounds (~104 copies/ml peaking at 5-12 days post-treatment. CD8+ cell depletion resulted in a more robust viral rebound (107 copies/ml that was controlled upon CD8+ T cell recovery. Our results show that RMD can reactivate SIV in vivo in the setting of post-ART viral control

Bioassay of circulating luteinizing hormone in the rhesus monkey: comparison with radioimmunoassay during physiological changes

International Nuclear Information System (INIS)

Dufau, M.L.; Hodgen, G.D.; Goodman, A.L.; Catt, K.J.

1977-01-01

The concentration of biologically active LH in Rhesus monkey (Macaca mulatta) serum was measured by a highly sensitive bioassay based upon testosterone production by dispersed rat interstitial cells. The sensitivity of the in vitro bioassay was equal to or higher than that of radioimmunoassay, with detection limits of 0.1 mIU of human menopausal gonadotropin (hMG) or 10 ng of a Rhesus pituitary gonadotropin preparation (LER-1909-2). Parallel dose-response curves were obtained for hMG and Rhesus monkey pituitary gonadotropin. The method permits bioassay of LH in 20--100 μl of serum from adult male monkeys, and from female monkeys during the follicular and luteal phases of the menstrual cycle. Bioactive LH concentrations could be assayed in 0.25 to 5 μl of serum from mid-cycle, postmenopausal, and castrated female monkeys. Serum LH was undetectable in two hypophysectomized adult female monkeys and six intact immature animals, and was 13 +- 6 (SD) mIU/ml in adult male monkeys. In adult females, follicular phase LH levels ranged from 17 to 169 mIU/ml, with a mean of 76 +- 52 mIU/ml. The midcycle LH peak was 1738 +- 742 mIU/ml and the luteal phase values ranged from 6-47 mIU/ml, with a mean of 35 +- 5 mIU/ml. Serum LH concentrations ranged from 100 to 900 mIU/ml in two menopausal females, and from 590--1480 mIU/ml in castrated females. Treatment of castrated female monkeys with estrogen plus progesterone produced an initial two-fold rise in sepum LH within 3 days, followed by a gradual decline to one-fourth to one-tenth of the initial levels after 10 days of treatment. Serum LH was suppressed to undetectable levels during the third week, and remained so for the duration of the 60-day treatment period

A Characterization of Aerosolized Sudan Virus Infection in African Green Monkeys, Cynomolgus Macaques, and Rhesus Macaques

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Donald K. Nichols

2012-10-01

Full Text Available Filoviruses are members of the genera Ebolavirus, Marburgvirus, and “Cuevavirus”. Because they cause human disease with high lethality and could potentially be used as a bioweapon, these viruses are classified as CDC Category A Bioterrorism Agents. Filoviruses are relatively stable in aerosols, retain virulence after lyophilization, and can be present on contaminated surfaces for extended periods of time. This study explores the characteristics of aerosolized Sudan virus (SUDV Boniface in non-human primates (NHP belonging to three different species. Groups of cynomolgus macaques (cyno, rhesus macaques (rhesus, and African green monkeys (AGM were challenged with target doses of 50 or 500 plaque-forming units (pfu of aerosolized SUDV. Exposure to either viral dose resulted in increased body temperatures in all three NHP species beginning on days 4–5 post-exposure. Other clinical findings for all three NHP species included leukocytosis, thrombocytopenia, anorexia, dehydration, and lymphadenopathy. Disease in all of the NHPs was severe beginning on day 6 post-exposure, and all animals except one surviving rhesus macaque were euthanized by day 14. Serum alanine transaminase (ALT and aspartate transaminase (AST concentrations were elevated during the course of disease in all three species; however, AGMs had significantly higher ALT and AST concentrations than cynos and rhesus. While all three species had detectable viral load by days 3-4 post exposure, Rhesus had lower average peak viral load than cynos or AGMs. Overall, the results indicate that the disease course after exposure to aerosolized SUDV is similar for all three species of NHP.

COMPARATIVE ANATOMY OF THE VITREOUS BODY IN RHESUS-MONKEYS AND MAN

NARCIS (Netherlands)

WORST, JGF; LOS, LI

1992-01-01

In the isolated unfixed vitreous body a structural organization can be visualized by slitlamp microscopy or by an ink-injection technique. We discuss the observations on human and rhesus monkey (Macaca mulatta) vitreous bodies using the ink-injection technique. Advantages and disadvantages of this

Hemopoietic stem cells in rhesus monkeys : surface antigens, radiosensitivity, and responses to GM-CSF

NARCIS (Netherlands)

J.J. Wielenga (Jenne)

1990-01-01

textabstractRhesus monkeys (Macaca mulatta) were bred at the Primate Center TNO, Rijswijk, The Netherlands!. Both male and female animals were used for the experiments. The monkeys weighed 2.5-4 kg and were 2-4 years old at the time of the experiment. They were all typed for RhLA-A, -B and -DR

Moderate Level Alcohol During Pregnancy, Prenatal Stress, or Both and Limbic-Hypothalamic-Pituitary-Adrenocortical Axis Response to Stress in Rhesus Monkeys

Science.gov (United States)

Schneider, Mary L.; Moore, Colleen F.; Kraemer, Gary W.

2004-01-01

This study examined the relationship between moderate-level prenatal alcohol exposure, prenatal stress, and postnatal response to a challenging event in 6-month-old rhesus monkeys. Forty-one rhesus monkey (Macaca mulatta) infants were exposed prenatally to moderate level alcohol, maternal stress, or both. Offspring plasma cortisol and…

Experimental allergic encephalomyelitis in rhesus monkeys: MR spectroscopy comparison with histopathology and ultrastructure

International Nuclear Information System (INIS)

Cao Qian; Wang Lianqing; Wu Jing; Zhao Huadong; Zhai Jinping; Guo Xue; Liu Lianxiang; Wu Yujin

2002-01-01

Objective: To study the relationships between changes of rhesus monkeys with EAE in MRS and those in histopathology and ultrastructure. Methods: Nine rhesus monkeys were sensitized by the intradermal injection of homologous myelin basic protein or purified bovine MBP in complete Freund's adjuvant. The ratio of Cho/Cr and NAA/Cr was measured in EAE over course and compared with that before attack. Finally, the histologic characters of the disease was confirmed by light microscope and transmission electron microscope. Results: The lesions of acute and chronic form of EAE was extensive. The lesions of chronic form of EAE observed on MRI were multiple and limited, with mild inflammation. The ratios of NAA/Cr in acute and chronic form were decreased (t = 68.66, 5.69, separately, P < 0.05). A lot of vacuolation, hydropic degeneration, and lipofuscin in the axis-cylinders could be observed in both phases. The ratio of Cho/Cr in chronic EAE was increased (t = 3.48, P < 0.05). In acute form of EAE, severe inflammation, necrosis, and destruction of axons were observed in histopathology. However, chronic form of EAE showed marked demyelination. Conclusion: The ratios of Cho/Cr and NAA/Cr by MRS quantitative analysis can be used to determine different stages of the lesion and predict the histopathological feature in EAE in rhesus monkeys

Phenobarbital treatments lower DDT body burden in rhesus monkeys

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Ferguson, P.W.; Clark, C.R.; Gee, S.J.; Krieger, R.I.

1981-01-01

Decreased DDT, DDD, DDE in blood and DDA in urine followed phenobarbital treatments (10 mg/kg/day, 11 days, intramuscular (im)) in three male rhesus monkeys (Macaca mulatta). Animals were fed DDT diets containing up to 500 ppm DDT during a 3-year period. Induction of liver monooxygenases was confirmed by reduced in vivo antipyrine plasma half-life and increased in vitro oxidation rates of dihydroisodrin, p-nitroanisole and benz(alpha)pyrene by homogenates of liver obtained from closed needle biopsy. Chlorohydrocarbon blood levels significantly decreased during the induction period (days 1-11). Concentrations on day 28 were at or below pre-DDT exposure levels. Urine DDA gradually decreased in all monkeys from days 16 to 28.

Peripheral refraction in normal infant rhesus monkeys

Science.gov (United States)

Hung, Li-Fang; Ramamirtham, Ramkumar; Huang, Juan; Qiao-Grider, Ying; Smith, Earl L.

2008-01-01

Purpose To characterize peripheral refractions in infant monkeys. Methods Cross-sectional data for horizontal refractions were obtained from 58 normal rhesus monkeys at 3 weeks of age. Longitudinal data were obtained for both the vertical and horizontal meridians from 17 monkeys. Refractive errors were measured by retinoscopy along the pupillary axis and at eccentricities of 15, 30, and 45 degrees. Axial dimensions and corneal power were measured by ultrasonography and keratometry, respectively. Results In infant monkeys, the degree of radial astigmatism increased symmetrically with eccentricity in all meridians. There were, however, initial nasal-temporal and superior-inferior asymmetries in the spherical-equivalent refractive errors. Specifically, the refractions in the temporal and superior fields were similar to the central ametropia, but the refractions in the nasal and inferior fields were more myopic than the central ametropia and the relative nasal field myopia increased with the degree of central hyperopia. With age, the degree of radial astigmatism decreased in all meridians and the refractions became more symmetrical along both the horizontal and vertical meridians; small degrees of relative myopia were evident in all fields. Conclusions As in adult humans, refractive error varied as a function of eccentricity in infant monkeys and the pattern of peripheral refraction varied with the central refractive error. With age, emmetropization occurred for both central and peripheral refractive errors resulting in similar refractions across the central 45 degrees of the visual field, which may reflect the actions of vision-dependent, growth-control mechanisms operating over a wide area of the posterior globe. PMID:18487366

Rhesus monkey lens as an in vitro model for studying oxidative stress

International Nuclear Information System (INIS)

Zigler, J.S. Jr.; Lucas, V.A.; Du, X.Y.

1989-01-01

Lenses from young rhesus monkeys were incubated in the presence of H 2 O 2 or oxygen radical generating systems to determine their suitability as a model for investigating lenticular oxidative stress. Additionally, direct comparisons were made between the effects found with the monkey lenses and those observed with cultured rat lenses exposed to the same oxidizing systems. As in earlier studies with rat lenses the monkey lenses exhibited impaired ability to actively accumulate from the medium radioactively labelled rubidium and choline following exposure to oxidative stress. Based on the effects of various scavengers of oxygen radicals it appeared that the mechanisms responsible for lens damage were the same for both rat and monkey lenses. However, rat lenses were damaged by lower concentrations of oxidants than were monkey lenses. It was concluded that oxidative stress affects both rat and monkey lenses by similar mechanisms but that lenses from monkeys, and probably other primates, are more resistant to these effects because they have better endogenous antioxidant defenses

Phylogeny and History of the Lost SIV from Crab-Eating Macaques: SIVmfa.

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Kevin R McCarthy

Full Text Available In the 20th century, thirteen distinct human immunodeficiency viruses emerged following independent cross-species transmission events involving simian immunodeficiency viruses (SIV from African primates. In the late 1900s, pathogenic SIV strains also emerged in the United Sates among captive Asian macaque species following their unintentional infection with SIV from African sooty mangabeys (SIVsmm. Since their discovery in the 1980s, SIVs from rhesus macaques (SIVmac and pig-tailed macaques (SIVmne have become invaluable models for studying HIV pathogenesis, vaccine design and the emergence of viruses. SIV isolates from captive crab-eating macaques (SIVmfa were initially described but lost prior to any detailed molecular and genetic characterization. In order to infer the origins of the lost SIVmfa lineage, we located archived material and colony records, recovered its genomic sequence by PCR, and assessed its phylogenetic relationship to other SIV strains. We conclude that SIVmfa is the product of two cross-species transmission events. The first was the established transmission of SIVsmm to rhesus macaques, which occurred at the California National Primate Research Center in the late 1960s and the virus later emerged as SIVmac. In a second event, SIVmac was transmitted to crab-eating macaques, likely at the Laboratory for Experimental Medicine and Surgery in Primates in the early 1970s, and it was later spread to the New England Primate Research Center colony in 1973 and eventually isolated in 1986. Our analysis suggests that SIVmac had already emerged by the early 1970s and had begun to diverge into distinct lineages. Furthermore, our findings suggest that pathogenic SIV strains may have been more widely distributed than previously appreciated, raising the possibility that additional isolates may await discovery.

Phylogeny and History of the Lost SIV from Crab-Eating Macaques: SIVmfa.

Science.gov (United States)

McCarthy, Kevin R; Johnson, Welkin E; Kirmaier, Andrea

2016-01-01

In the 20th century, thirteen distinct human immunodeficiency viruses emerged following independent cross-species transmission events involving simian immunodeficiency viruses (SIV) from African primates. In the late 1900s, pathogenic SIV strains also emerged in the United Sates among captive Asian macaque species following their unintentional infection with SIV from African sooty mangabeys (SIVsmm). Since their discovery in the 1980s, SIVs from rhesus macaques (SIVmac) and pig-tailed macaques (SIVmne) have become invaluable models for studying HIV pathogenesis, vaccine design and the emergence of viruses. SIV isolates from captive crab-eating macaques (SIVmfa) were initially described but lost prior to any detailed molecular and genetic characterization. In order to infer the origins of the lost SIVmfa lineage, we located archived material and colony records, recovered its genomic sequence by PCR, and assessed its phylogenetic relationship to other SIV strains. We conclude that SIVmfa is the product of two cross-species transmission events. The first was the established transmission of SIVsmm to rhesus macaques, which occurred at the California National Primate Research Center in the late 1960s and the virus later emerged as SIVmac. In a second event, SIVmac was transmitted to crab-eating macaques, likely at the Laboratory for Experimental Medicine and Surgery in Primates in the early 1970s, and it was later spread to the New England Primate Research Center colony in 1973 and eventually isolated in 1986. Our analysis suggests that SIVmac had already emerged by the early 1970s and had begun to diverge into distinct lineages. Furthermore, our findings suggest that pathogenic SIV strains may have been more widely distributed than previously appreciated, raising the possibility that additional isolates may await discovery.

Food intake and meal patterns in rhesus monkeys: Significance of chronic hyperinsulinemia

International Nuclear Information System (INIS)

Hannah, J.; Hansen, B.C.

1990-01-01

To investigate the role of plasma insulin on food intake, we have examined the effect of naturally occurring chronic hyperinsulinemia on the feeding behavior of male rhesus monkeys. Two groups of monkeys, a group with normal fasting insulin concentrations (52.4 +/- 2.2 microU/ml) (mean +/- SE) and a hyperinsulinemic group (148.6 +/- 14.5 microU/ml), were selected to be similar in weight, 13.0 +/- 1.0 and 15.3 +/- 0.5 kg, respectively, prior to study. Food intake and feeding patterns were recorded and analyzed. No differences in either daily caloric intake, 815.2 +/- 27.4 versus 890.0 +/- 64.2 kcal (p less than 0.32), or feeding patterns were found. The number of meals taken per day did not differ between the two groups, 8.7 +/- 1.7 versus 6.7 +/- 1.1 (p less than 0.35), nor did meal size differ, 129 +/- 16.5 versus 110.5 +/- 16.3 (p less than 0.45). We conclude that chronic endogenous hyperinsulinemia as it occurs naturally in some obese rhesus monkeys has no significant effect on daily feeding behavior

Simian virus 40 inhibits differentiation and maturation of rhesus macaque DC-SIGN+-dendritic cells

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Changyong G

2010-09-01

Full Text Available Abstract Dendritic cells (DC are the initiators and modulators of the immune responses. Some species of pathogenic microorganisms have developed immune evasion strategies by controlling antigen presentation function of DC. Simian virus 40 (SV40 is a DNA tumor virus of rhesus monkey origin. It can induce cell transformation and tumorigenesis in many vertebrate species, but often causes no visible effects and persists as a latent infection in rhesus monkeys under natural conditions. To investigate the interaction between SV40 and rhesus monkey DC, rhesus monkey peripheral blood monocyte-derived DC were induced using recombinant human Interleukin-4 (rhIL-4 and infective SV40, the phenotype and function of DC-specific intracellular adhesion molecule-3 grabbing nonintegrin (DC-SIGN+ DC were analyzed by flow cytometry (FCM and mixed lymphocyte reaction (MLR. Results showed that SV40 can down-regulate the expression of CD83 and CD86 on DC and impair DC-induced activation of T cell proliferation. These findings suggest that SV40 might also cause immune suppression by influencing differentiation and maturation of DC.

Spermatogenesis in adult rhesus monkeys following irradiation with X-rays or fission neutrons

International Nuclear Information System (INIS)

Rooij, D.G. de; Sonneveld, P.; Bekkum, D.W. van

A group of male rhesus monkeys was exposed to total body irradiation followed by autologous bone marrow transplantation. The animals were irradiated in the period between 1965 and 1976 and received a dose of 8.5 Gy of X-rays (300 KVP) or 3.6 Gy of 1 MeV fission neutrons. Of this group, a total of 11 male monkeys proved to be evaluable for studying the effects of irradiation on spermatogenesis. (Auth.)

Production of rhesus monkey cloned embryos expressing monomeric red fluorescent protein by interspecies somatic cell nuclear transfer

International Nuclear Information System (INIS)

Zhu, Hai-Ying; Kang, Jin-Dan; Li, Suo; Jin, Jun-Xue; Hong, Yu; Jin, Long; Guo, Qing; Gao, Qing-Shan; Yan, Chang-Guo; Yin, Xi-Jun

2014-01-01

Highlights: • Rhesus monkey cells were electroporated with a plasmid containing mRFP1, and an mRFP1-expressing cell line was generated. • For the first time, mRFP1-expressing rhesus monkey cells were used as donor cells for iSCNT. • The effect of VPA on the development of embryos cloned using iSCNT was determined. - Abstract: Interspecies somatic cell nuclear transfer (iSCNT) is a promising method to clone endangered animals from which oocytes are difficult to obtain. Monomeric red fluorescent protein 1 (mRFP1) is an excellent selection marker for transgenically modified cloned embryos during somatic cell nuclear transfer (SCNT). In this study, mRFP-expressing rhesus monkey cells or porcine cells were transferred into enucleated porcine oocytes to generate iSCNT and SCNT embryos, respectively. The development of these embryos was studied in vitro. The percentage of embryos that underwent cleavage did not significantly differ between iSCNT and SCNT embryos (P > 0.05; 71.53% vs. 80.30%). However, significantly fewer iSCNT embryos than SCNT embryos reached the blastocyst stage (2.04% vs. 10.19%, P < 0.05). Valproic acid was used in an attempt to increase the percentage of iSCNT embryos that developed to the blastocyst stage. However, the percentages of embryos that underwent cleavage and reached the blastocyst stage were similar between untreated iSCNT embryos and iSCNT embryos treated with 2 mM valproic acid for 24 h (72.12% vs. 70.83% and 2.67% vs. 2.35%, respectively). These data suggest that porcine-rhesus monkey interspecies embryos can be generated that efficiently express mRFP1. However, a significantly lower proportion of iSCNT embryos than SCNT embryos reach the blastocyst stage. Valproic acid does not increase the percentage of porcine-rhesus monkey iSCNT embryos that reach the blastocyst stage. The mechanisms underling nuclear reprogramming and epigenetic modifications in iSCNT need to be investigated further

Production of rhesus monkey cloned embryos expressing monomeric red fluorescent protein by interspecies somatic cell nuclear transfer

Energy Technology Data Exchange (ETDEWEB)

Zhu, Hai-Ying; Kang, Jin-Dan; Li, Suo; Jin, Jun-Xue; Hong, Yu; Jin, Long; Guo, Qing; Gao, Qing-Shan; Yan, Chang-Guo; Yin, Xi-Jun, E-mail: yinxj33@msn.com

2014-02-21

Highlights: • Rhesus monkey cells were electroporated with a plasmid containing mRFP1, and an mRFP1-expressing cell line was generated. • For the first time, mRFP1-expressing rhesus monkey cells were used as donor cells for iSCNT. • The effect of VPA on the development of embryos cloned using iSCNT was determined. - Abstract: Interspecies somatic cell nuclear transfer (iSCNT) is a promising method to clone endangered animals from which oocytes are difficult to obtain. Monomeric red fluorescent protein 1 (mRFP1) is an excellent selection marker for transgenically modified cloned embryos during somatic cell nuclear transfer (SCNT). In this study, mRFP-expressing rhesus monkey cells or porcine cells were transferred into enucleated porcine oocytes to generate iSCNT and SCNT embryos, respectively. The development of these embryos was studied in vitro. The percentage of embryos that underwent cleavage did not significantly differ between iSCNT and SCNT embryos (P > 0.05; 71.53% vs. 80.30%). However, significantly fewer iSCNT embryos than SCNT embryos reached the blastocyst stage (2.04% vs. 10.19%, P < 0.05). Valproic acid was used in an attempt to increase the percentage of iSCNT embryos that developed to the blastocyst stage. However, the percentages of embryos that underwent cleavage and reached the blastocyst stage were similar between untreated iSCNT embryos and iSCNT embryos treated with 2 mM valproic acid for 24 h (72.12% vs. 70.83% and 2.67% vs. 2.35%, respectively). These data suggest that porcine-rhesus monkey interspecies embryos can be generated that efficiently express mRFP1. However, a significantly lower proportion of iSCNT embryos than SCNT embryos reach the blastocyst stage. Valproic acid does not increase the percentage of porcine-rhesus monkey iSCNT embryos that reach the blastocyst stage. The mechanisms underling nuclear reprogramming and epigenetic modifications in iSCNT need to be investigated further.

Sex differences in rhesus monkey toy preferences parallel those of children

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Hassett, Janice M.; Siebert, Erin R.; Wallen, Kim

2008-01-01

Socialization processes, parents, or peers encouraging play with gender specific toys are thought to be the primary force shaping sex differences in toy preference. A contrast in view is that toy preferences reflect biologically determined preferences for specific activities facilitated by specific toys. Sex differences in juvenile activities, such as rough and tumble play, peer preferences, and infant interest, share similarities in humans and monkeys. Thus if activity preferences shape toy preferences, male and female monkeys may show toy preferences similar to those seen in boys and girls. We compared the interactions of 34 rhesus monkeys, living within a 135 monkey troop, with human wheeled toys and plush toys. Male monkeys, like boys, showed consistent and strong preferences for wheeled toys, while female monkeys, like girls, showed greater variability in preferences. Thus, the magnitude of preference for wheeled over plush toys differed significantly between males and females. The similarities to human findings demonstrate that such preferences can develop without explicit gendered socialization. We offer the hypothesis that toy preferences reflect hormonally influenced behavioral and cognitive biases which are sculpted by social processes into the sex differences seen in monkeys and humans. PMID:18452921

Rhesus monkeys attribute perceptions to others.

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Flombaum, Jonathan I; Santos, Laurie R

2005-03-08

Paramount among human cognitive abilities is the capacity to reason about what others think, want, and see--a capacity referred to as a theory of mind (ToM). Despite its importance in human cognition, the extent to which other primates share human ToM capacities has for decades remained a mystery. To date, primates [1, 2] have performed poorly in behavioral tasks that require ToM abilities, despite the fact that some macaques are known to encode social stimuli at the level of single neurons [3-5]. Here, we presented rhesus macaques with a more ecologically relevant ToM task in which subjects could "steal" a contested grape from one of two human competitors. In six experiments, monkeys selectively retrieved the grape from an experimenter who was incapable of seeing the grape rather than an experimenter who was visually aware. These results suggest that rhesus macaques possess an essential component of ToM: the ability to deduce what others perceive on the basis of where they are looking. These results converge with new findings illustrating the importance of competitive paradigms in apes [6]. Moreover, they raise the possibility that, in primates, cortical cells thought to encode where others are looking [7] may encode what those individuals see as well.

Epigenetic mechanism underlying the development of polycystic ovary syndrome (PCOS)-like phenotypes in prenatally androgenized rhesus monkeys.

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Xu, Ning; Kwon, Soonil; Abbott, David H; Geller, David H; Dumesic, Daniel A; Azziz, Ricardo; Guo, Xiuqing; Goodarzi, Mark O

2011-01-01

The pathogenesis of polycystic ovary syndrome (PCOS) is poorly understood. PCOS-like phenotypes are produced by prenatal androgenization (PA) of female rhesus monkeys. We hypothesize that perturbation of the epigenome, through altered DNA methylation, is one of the mechanisms whereby PA reprograms monkeys to develop PCOS. Infant and adult visceral adipose tissues (VAT) harvested from 15 PA and 10 control monkeys were studied. Bisulfite treated samples were subjected to genome-wide CpG methylation analysis, designed to simultaneously measure methylation levels at 27,578 CpG sites. Analysis was carried out using Bayesian Classification with Singular Value Decomposition (BCSVD), testing all probes simultaneously in a single test. Stringent criteria were then applied to filter out invalid probes due to sequence dissimilarities between human probes and monkey DNA, and then mapped to the rhesus genome. This yielded differentially methylated loci between PA and control monkeys, 163 in infant VAT, and 325 in adult VAT (BCSVD Pexcess fetal androgen exposure in female nonhuman primates may predispose to PCOS via alteration of the epigenome, providing a novel avenue to understand PCOS in humans.

Dissociation of item and source memory in rhesus monkeys.

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Basile, Benjamin M; Hampton, Robert R

2017-09-01

Source memory, or memory for the context in which a memory was formed, is a defining characteristic of human episodic memory and source memory errors are a debilitating symptom of memory dysfunction. Evidence for source memory in nonhuman primates is sparse despite considerable evidence for other types of sophisticated memory and the practical need for good models of episodic memory in nonhuman primates. A previous study showed that rhesus monkeys confused the identity of a monkey they saw with a monkey they heard, but only after an extended memory delay. This suggests that they initially remembered the source - visual or auditory - of the information but forgot the source as time passed. Here, we present a monkey model of source memory that is based on this previous study. In each trial, monkeys studied two images, one that they simply viewed and touched and the other that they classified as a bird, fish, flower, or person. In a subsequent memory test, they were required to select the image from one source but avoid the other. With training, monkeys learned to suppress responding to images from the to-be-avoided source. After longer memory intervals, monkeys continued to show reliable item memory, discriminating studied images from distractors, but made many source memory errors. Monkeys discriminated source based on study method, not study order, providing preliminary evidence that our manipulation of retention interval caused errors due to source forgetting instead of source confusion. Finally, some monkeys learned to select remembered images from either source on cue, showing that they did indeed remember both items and both sources. This paradigm potentially provides a new model to study a critical aspect of episodic memory in nonhuman primates. Copyright © 2017 Elsevier B.V. All rights reserved.

Lifetime effects of single-event proton exposures in rhesus monkeys

International Nuclear Information System (INIS)

Wood, D.H.; Yochmowitz, M.G.; Salmon, Y.L.

1986-01-01

The US School of Aerospace Medicine studies of the lifetime effects of proton irradiation in rhesus monkeys have been conducted. Life-span shortening has been associated with proton energies of 55 MeV and above, as well as with doses greater than 360 rads. Female rhesus monkeys have a higher mortality than males as a result of high incidence of endometriosis in the irradiated animals. A dose ordering effect is apparent. Mortality rates began to accelerate at eight years after doses of 360 to 400 rads; at two years, after 500 to 650 rads; and less than one year, after 800 rads. Malignant tumors accounted for 18% of the deaths in the proton-exposed animals. Endometriosis was the cause of 25% of the deaths in this group. Energy-specific effects were observed. Eight malignant brain tumors occurred in animals exposed to 55-MeV protons and in no other group. Cataract incidence was highest in animals exposed to 32 and 55 MeV. These observations suggest a positive relationship with the Bragg peak energy distribution in the area of the brain and crystalline lens. Glucose tolerance was lowest in the animals exposed to totally penetrating radiation, where the fraction of the surface dose reaching the pancreas was highest. Age-matched control animals have yet to pass their median survival time, and the colony continues to be a valuable source of data on the relationship of total-body radiation to age-related diseases in captive monkeys. 16 refs., 6 figs., 5 tabs

Effect of whole-body irradiation on skeletal growth in rhesus monkeys

International Nuclear Information System (INIS)

Sonneveld, P.; van Bekkum, D.W.

1979-01-01

Late effects of single whole-body doses of 400 to 500 and 750 to 900 rads on skeletal growth in 32 rhesus monkeys were studied. Findings indicated growth inhibition strongly related to dose and age at irradiation. Doses of 750 to 900 rads before the age of 40 months resulted in significantly greater growth inhibition (11%) than doses given during or shortly after adolescence (p < 0.005). Doses of less than 750 rads were not significant. In view of the close similarity between monkeys and man, irradiation of children at doses greater than 750 rads may carry a strong risk of subsequent growth retardation

Intranasal oxytocin enhances socially-reinforced learning in rhesus monkeys

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Lisa A Parr

2014-09-01

Full Text Available There are currently no drugs approved for the treatment of social deficits associated with autism spectrum disorders (ASD. One hypothesis for these deficits is that individuals with ASD lack the motivation to attend to social cues because those cues are not implicitly rewarding. Therefore, any drug that could enhance the rewarding quality of social stimuli could have a profound impact on the treatment of ASD, and other social disorders. Oxytocin (OT is a neuropeptide that has been effective in enhancing social cognition and social reward in humans. The present study examined the ability of OT to selectively enhance learning after social compared to nonsocial reward in rhesus monkeys, an important species for modeling the neurobiology of social behavior in humans. Monkeys were required to learn an implicit visual matching task after receiving either intranasal (IN OT or Placebo (saline. Correct trials were rewarded with the presentation of positive and negative social (play faces/threat faces or nonsocial (banana/cage locks stimuli, plus food. Incorrect trials were not rewarded. Results demonstrated a strong effect of socially-reinforced learning, monkeys’ performed significantly better when reinforced with social versus nonsocial stimuli. Additionally, socially-reinforced learning was significantly better and occurred faster after IN-OT compared to placebo treatment. Performance in the IN-OT, but not Placebo, condition was also significantly better when the reinforcement stimuli were emotionally positive compared to negative facial expressions. These data support the hypothesis that OT may function to enhance prosocial behavior in primates by increasing the rewarding quality of emotionally positive, social compared to emotionally negative or nonsocial images. These data also support the use of the rhesus monkey as a model for exploring the neurobiological basis of social behavior and its impairment.

Protection of macaques with diverse MHC genotypes against a heterologous SIV by vaccination with a deglycosylated live-attenuated SIV.

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Chie Sugimoto

Full Text Available HIV vaccine development has been hampered by issues such as undefined correlates of protection and extensive diversity of HIV. We addressed these issues using a previously established SIV-macaque model in which SIV mutants with deletions of multiple gp120 N-glycans function as potent live attenuated vaccines to induce near-sterile immunity against the parental pathogenic SIVmac239. In this study, we investigated the protective efficacy of these mutants against a highly pathogenic heterologous SIVsmE543-3 delivered intravenously to rhesus macaques with diverse MHC genotypes. All 11 vaccinated macaques contained the acute-phase infection with blood viral loads below the level of detection between 4 and 10 weeks postchallenge (pc, following a transient but marginal peak of viral replication at 2 weeks in only half of the challenged animals. In the chronic phase, seven vaccinees contained viral replication for over 80 weeks pc, while four did not. Neutralizing antibodies against challenge virus were not detected. Although overall levels of SIV specific T cell responses did not correlate with containment of acute and chronic viral replication, a critical role of cellular responses in the containment of viral replication was suggested. Emergence of viruses with altered fitness due to recombination between the vaccine and challenge viruses and increased gp120 glycosylation was linked to the failure to control SIV. These results demonstrate the induction of effective protective immune responses in a significant number of animals against heterologous virus by infection with deglycosylated attenuated SIV mutants in macaques with highly diverse MHC background. These findings suggest that broad HIV cross clade protection is possible, even in hosts with diverse genetic backgrounds. In summary, results of this study indicate that deglycosylated live-attenuated vaccines may provide a platform for the elucidation of correlates of protection needed for a

Empty Sets as Part of the Numerical Continuum: Conceptual Precursors to the Zero Concept in Rhesus Monkeys

Science.gov (United States)

Merritt, Dustin J.; Rugani, Rosa; Brannon, Elizabeth M.

2009-01-01

The goal of the current research was to explore whether monkeys possess conceptual precursors necessary for understanding zero. We trained rhesus monkeys on a nonsymbolic numerical matching-to-sample task, and on a numerical ordering task. We then introduced nondifferentially reinforced trials that contained empty sets to determine whether monkeys…

Exploring decoy effects on computerized task preferences in rhesus monkeys (Macaca mulatta.

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Audrey E. Parrish

2018-05-01

Full Text Available The asymmetric dominance effect or decoy effect emerges when a third inferior option is introduced to a choice set. The decoy option, although typically not chosen, impacts relative preference for the original two options. This decisional bias stands in contrast with rational choice theory, which dictates that choice behavior should remain consistent for the original options with the addition of different alternatives to a choice set such as the decoy. In the current study, we assessed the decoy effect in rhesus monkeys using a computerized task battery that introduced two different computerized tasks, including a matching-to-sample task and a psychomotor task called PURSUIT. Decoy tasks were designed such that they were inferior versions of these original task options, requiring longer time to completion (via slowed cursor speeds and subsequently reduced reinforcement rates. Monkeys learned to associate unique icons for each task (including for decoy tasks, and used these icons to select their preferred task from a choice set of two to three task options. Monkeys learned to perform all tasks, but did not show evidence of the decoy effect using this task preference paradigm. We discuss the role of initial task preference (and task biases, task type (symbolic vs. perceptual, and decoy effect sizes in light of these findings. We contrast the current results to previous findings of the decoy effect in rhesus monkeys using a perceptual paradigm as well as to other evidence of the decoy effect in non-primate animal species.

The rhesus monkey (Macaca mulatta) as a flight candidate

Science.gov (United States)

Debourne, M. N. G.; Bourne, G. H.; Mcclure, H. M.

1977-01-01

The intelligence and ruggedness of rhesus monkeys, as well as the abundance of normative data on their anatomy, physiology, and biochemistry, and the availability of captive bred animals qualify them for selection as candidates for orbital flight and weightlessness studies. Baseline data discussed include: physical characteristics, auditory thresholds, visual accuity, blood, serological taxomony, immunogenetics, cytogenics, circadian rhythms, respiration, cardiovascular values, corticosteroid response to charr restraint, microscopy of tissues, pathology, nutrition, and learning skills. Results from various tests used to establish the baseline data are presented in tables.

Intrapericardial Denervation: Responses to Water Immersion in Rhesus Monkeys

Science.gov (United States)

McKeever, Kenneth H.; Keil, Lanny C.; Sandler, Harold

1995-01-01

Eleven anesthetized rhesus monkeys were used to study cardiovascular, renal, and endocrine alterations associated with 120 min of head-out water immersion. Five animals underwent complete intrapericardial denervation using the Randall technique, while the remaining six monkeys served as intact controls. Each animal was chronically instrumented with an electromagnetic flow probe on the ascending aorta, a strain gauge pressure transducer implanted in the apex of the left ventricle (LV), and electrocardiogram leads anchored to the chest wall and LV. During immersion, LV end-diastolic pressure, urine flow, glomerular filtration rate, sodium excretion, and circulating atrial natriuretic peptide (ANP) each increased (P less than 0.05) for intact and denervated monkeys. There were no alterations in free water clearance in either group during immersion, yet fractional excretion of free water increased (P less than 0.05) in the intact monkeys. Plasma renin activity (PRA) decreased (P less than 0.05) during immersion in intact monkeys but not the denervated animals. Plasma vasopressin (PVP) concentration decreased (P less than 0.05) during the first 30 min of immersion in both groups but was not distinguishable from control by 60 min of immersion in denervated monkeys. These data demonstrate that complete cardiac denervation does not block the rise in plasma ANP or prevent the natriuresis associated with head-out water immersion. The suppression of PVP during the first minutes of immersion after complete cardiac denervation suggests that extracardiac sensing mechanisms associated with the induced fluid shifts may be responsible for the findings.

Dosimetry for total body irradiation of rhesus monkeys with 300 kV X- rays

NARCIS (Netherlands)

Zoetelief, J.; Wagemaker, G.; Broerse, J.J.

1998-01-01

Purpose: To obtain more accurate information on the dose distribution in rhesus monkeys for total body irradiation with orthovoltage X-rays. Materials and methods: Dose measurements were performed with an ionization chamber inside homogeneous cylindrical and rectangular phantoms of various

Genetically-barcoded SIV facilitates enumeration of rebound variants and estimation of reactivation rates in nonhuman primates following interruption of suppressive antiretroviral therapy.

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Christine M Fennessey

2017-05-01

Full Text Available HIV and SIV infection dynamics are commonly investigated by measuring plasma viral loads. However, this total viral load value represents the sum of many individual infection events, which are difficult to independently track using conventional sequencing approaches. To overcome this challenge, we generated a genetically tagged virus stock (SIVmac239M with a 34-base genetic barcode inserted between the vpx and vpr accessory genes of the infectious molecular clone SIVmac239. Next-generation sequencing of the virus stock identified at least 9,336 individual barcodes, or clonotypes, with an average genetic distance of 7 bases between any two barcodes. In vitro infection of rhesus CD4+ T cells and in vivo infection of rhesus macaques revealed levels of viral replication of SIVmac239M comparable to parental SIVmac239. After intravenous inoculation of 2.2x105 infectious units of SIVmac239M, an average of 1,247 barcodes were identified during acute infection in 26 infected rhesus macaques. Of the barcodes identified in the stock, at least 85.6% actively replicated in at least one animal, and on average each barcode was found in 5 monkeys. Four infected animals were treated with combination antiretroviral therapy (cART for 82 days starting on day 6 post-infection (study 1. Plasma viremia was reduced from >106 to <15 vRNA copies/mL by the time treatment was interrupted. Virus rapidly rebounded following treatment interruption and between 87 and 136 distinct clonotypes were detected in plasma at peak rebound viremia. This study confirmed that SIVmac239M viremia could be successfully curtailed with cART, and that upon cART discontinuation, rebounding viral variants could be identified and quantified. An additional 6 animals infected with SIVmac239M were treated with cART beginning on day 4 post-infection for 305, 374, or 482 days (study 2. Upon treatment interruption, between 4 and 8 distinct viral clonotypes were detected in each animal at peak rebound

Semen CD4+ T Cells and Macrophages Are Productively Infected at All Stages of SIV infection in Macaques

Science.gov (United States)

Bernard-Stoecklin, Sibylle; Gommet, Céline; Corneau, Aurélien B.; Guenounou, Sabrina; Torres, Claire; Dejucq-Rainsford, Nathalie; Cosma, Antonio; Dereuddre-Bosquet, Nathalie; Le Grand, Roger

2013-01-01

The mucosal events of HIV transmission have been extensively studied, but the role of infected cells present in the genital and rectal secretions, and in the semen, in particular, remains a matter of debate. As a prerequisite to a thorough in vivo investigation of the early transmission events through infected cells, we characterized in detail by multi-parameter flow cytometry the changes in macaque seminal leukocytes during SIVmac251 infection, focusing on T cells, macrophages and dendritic cells. Using immunocytofluorescence targeting SIV proteins and real-time quantitative PCR targeting SIV DNA, we investigated the nature of the infected cells on sorted semen leukocytes from macaques at different stages of infection. Finally, we cocultured semen CD4+ T cells and macrophages with a cell line permissive to SIV infection to assess their infectivity in vitro. We found that primary infection induced strong local inflammation, which was associated with an increase in the number of leukocytes in semen, both factors having the potential to favor cell-associated virus transmission. Semen CD4+ T cells and macrophages were productively infected at all stages of infection and were infectious in vitro. Lymphocytes had a mucosal phenotype and expressed activation (CD69 & HLA-DR) and migration (CCR5, CXCR4, LFA-1) markers. CD69 expression was increased in semen T cells by SIV infection, at all stages of infection. Macrophages predominated at all stages and expressed CD4, CCR5, MAC-1 and LFA-1. Altogether, we demonstrated that semen contains the two major SIV-target cells (CD4+ T cells and macrophages). Both cell types can be productively infected at all stages of SIV infection and are endowed with markers that may facilitate transmission of infection during sexual exposure. PMID:24348253

Attenuation and immunogenicity of recombinant yellow fever 17D-dengue type 2 virus for rhesus monkeys

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Galler R.

2005-01-01

Full Text Available A chimeric yellow fever (YF-dengue serotype 2 (dengue 2 virus was constructed by replacing the premembrane and envelope genes of the YF 17D virus with those from dengue 2 virus strains of Southeast Asian genotype. The virus grew to high titers in Vero cells and, after passage 2, was used for immunogenicity and attenuation studies in rhesus monkeys. Subcutaneous immunization of naive rhesus monkeys with the 17D-D2 chimeric virus induced a neutralizing antibody response associated with the protection of 6 of 7 monkeys against viremia by wild-type dengue 2 virus. Neutralizing antibody titers to dengue 2 were significantly lower in YF-immune animals than in YF-naive monkeys and protection against challenge with wild-type dengue 2 virus was observed in only 2 of 11 YF-immune monkeys. An anamnestic response to dengue 2, indicated by a sharp increase of neutralizing antibody titers, was observed in the majority of the monkeys after challenge with wild-type virus. Virus attenuation was demonstrated using the standard monkey neurovirulence test. The 17D-D2 chimera caused significantly fewer histological lesions than the YF 17DD virus. The attenuated phenotype could also be inferred from the limited viremias compared to the YF 17DD vaccine. Overall, these results provide further support for the use of chimeric viruses for the development of a new live tetravalent dengue vaccine.

Event-based proactive interference in rhesus monkeys.

Science.gov (United States)

Devkar, Deepna T; Wright, Anthony A

2016-10-01

Three rhesus monkeys (Macaca mulatta) were tested in a same/different memory task for proactive interference (PI) from prior trials. PI occurs when a previous sample stimulus appears as a test stimulus on a later trial, does not match the current sample stimulus, and the wrong response "same" is made. Trial-unique pictures (scenes, objects, animals, etc.) were used on most trials, except on trials where the test stimulus matched potentially interfering sample stimulus from a prior trial (1, 2, 4, 8, or 16 trials prior). Greater interference occurred when fewer trials separated interference and test. PI functions showed a continuum of interference. Delays between sample and test stimuli and intertrial intervals were manipulated to test how PI might vary as a function of elapsed time. Contrary to a similar study with pigeons, these time manipulations had no discernable effect on the monkey's PI, as shown by compete overlap of PI functions with no statistical differences or interactions. These results suggested that interference was strictly based upon the number of intervening events (trials with other pictures) without regard to elapsed time. The monkeys' apparent event-based interference was further supported by retesting with a novel set of 1,024 pictures. PI from novel pictures 1 or 2 trials prior was greater than from familiar pictures, a familiar set of 1,024 pictures. Moreover, when potentially interfering novel stimuli were 16 trials prior, performance accuracy was actually greater than accuracy on baseline trials (no interference), suggesting that remembering stimuli from 16 trials prior was a cue that this stimulus was not the sample stimulus on the current trial-a somewhat surprising conclusion particularly given monkeys.

Interactive effects of morphine and dopaminergic compounds on spatial working memory in rhesus monkeys

Institute of Scientific and Technical Information of China (English)

Jian-Hong Wang; Joshua Dominie Rizak; Yan-Mei Chen; Liang Li; Xin-Tian Hu; Yuan-Ye Ma

2013-01-01

Opiates and dopamine (DA) play key roles in learning and memory in humans and animals.Although interactions between these neurotransmitters have been found,their functional roles remain to be fully elucidated,and their dysfunction may contribute to human diseases and addiction.Here we investigated the interactions of morphine and dopaminergic neurotransmitter systems with respect to learning and memory in rhesus monkeys by using the Wisconsin General Test Apparatus (WGTA) delayed-response task.Morphine and DA agonists (SKF-38393,apomorphine and bromocriptine) or DA antagonists (SKF-83566,haloperidol and sulpiride) were co-administered to the monkeys 30 min prior to the task.We found that dose-patterned co-administration of morphine with D1 or D2 antagonists or agonists reversed the impaired spatial working memory induced by morphine or the compounds alone.For example,morphine at 0.01 mg/kg impaired spatial working memory,while morphine (0.01 mg/kg) and apomorphine (0.01 or 0.06 mg/kg) co-treatment ameliorated this effect.Our findings suggest that the interactions between morphine and dopaminergic compounds influence spatial working memory in rhesus monkeys.A better understanding of these interactive relationships may provide insights into human addiction.

Do you see what I see? A comparative investigation of the Delboeuf illusion in humans (Homo sapiens), rhesus monkeys (Macaca mulatta), and capuchin monkeys (Cebus apella).

Science.gov (United States)

Parrish, Audrey E; Brosnan, Sarah F; Beran, Michael J

2015-10-01

Studying visual illusions is critical to understanding typical visual perception. We investigated whether rhesus monkeys (Macaca mulatta) and capuchin monkeys (Cebus apella) perceived the Delboeuf illusion in a similar manner as human adults (Homo sapiens). To test this, in Experiment 1, we presented monkeys and humans with a relative discrimination task that required subjects to choose the larger of 2 central dots that were sometimes encircled by concentric rings. As predicted, humans demonstrated evidence of the Delboeuf illusion, overestimating central dots when small rings surrounded them and underestimating the size of central dots when large rings surrounded them. However, monkeys did not show evidence of the illusion. To rule out an alternate explanation, in Experiment 2, we presented all species with an absolute classification task that required them to classify a central dot as "small" or "large." We presented a range of ring sizes to determine whether the Delboeuf illusion would occur for any dot-to-ring ratios. Here, we found evidence of the Delboeuf illusion in all 3 species. Humans and monkeys underestimated central dot size to a progressively greater degree with progressively larger rings. The Delboeuf illusion now has been extended to include capuchin monkeys and rhesus monkeys, and through such comparative investigations we can better evaluate hypotheses regarding illusion perception among nonhuman animals. (c) 2015 APA, all rights reserved).

Nutritional manipulation of primate retinas, I: effects of lutein or zeaxanthin supplements on serum and macular pigment in xanthophyll-free rhesus monkeys.

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Neuringer, Martha; Sandstrom, Marita M; Johnson, Elizabeth J; Snodderly, D Max

2004-09-01

The xanthophylls lutein (L) and zeaxanthin (Z) are the primary components of macular pigment (MP) and may protect the macula from age-related degeneration (AMD). In this study, L or Z was fed to rhesus monkeys reared on xanthophyll-free diets to follow the accumulation of serum carotenoids and MP over time. Eighteen rhesus monkeys were fed xanthophyll-free semipurified diets from birth until 7 to 16 years. The diets of six were then supplemented with pure L and six with pure Z at 3.9 micromol/kg per day (2.2 mg/kg per day) for 24 to 56 weeks. At baseline and 4- to 12-week intervals during supplementation, serum carotenoids were measured by HPLC, and MP density was estimated by two-wavelength reflectometry. Serum carotenoids and MP were also measured in monkeys fed a stock diet. Monkeys fed xanthophyll-free diets had no L or Z in serum and no detectable MP. During supplementation, serum L or Z increased rapidly over the first 4 weeks and from 16 weeks onward maintained similar levels, both several times higher than in stock-diet-fed monkeys. The central peak of MP optical density increased to a relatively steady level by 24 to 32 weeks in both L- and Z-fed groups. Rhesus monkeys fed a stock diet had lower blood concentrations of L than those found in humans and other nonhuman primates. Rhesus monkeys respond to either dietary L or Z supplementation with increases in serum xanthophylls and MP, even after life-long xanthophyll deficiency. These animals provide a potential model to study mechanisms of protection from AMD. Copyright Association for Research in Vision and Ophthalmology

Face Pareidolia in the Rhesus Monkey.

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Taubert, Jessica; Wardle, Susan G; Flessert, Molly; Leopold, David A; Ungerleider, Leslie G

2017-08-21

Face perception in humans and nonhuman primates is rapid and accurate [1-4]. In the human brain, a network of visual-processing regions is specialized for faces [5-7]. Although face processing is a priority of the primate visual system, face detection is not infallible. Face pareidolia is the compelling illusion of perceiving facial features on inanimate objects, such as the illusory face on the surface of the moon. Although face pareidolia is commonly experienced by humans, its presence in other species is unknown. Here we provide evidence for face pareidolia in a species known to possess a complex face-processing system [8-10]: the rhesus monkey (Macaca mulatta). In a visual preference task [11, 12], monkeys looked longer at photographs of objects that elicited face pareidolia in human observers than at photographs of similar objects that did not elicit illusory faces. Examination of eye movements revealed that monkeys fixated the illusory internal facial features in a pattern consistent with how they view photographs of faces [13]. Although the specialized response to faces observed in humans [1, 3, 5-7, 14] is often argued to be continuous across primates [4, 15], it was previously unclear whether face pareidolia arose from a uniquely human capacity. For example, pareidolia could be a product of the human aptitude for perceptual abstraction or result from frequent exposure to cartoons and illustrations that anthropomorphize inanimate objects. Instead, our results indicate that the perception of illusory facial features on inanimate objects is driven by a broadly tuned face-detection mechanism that we share with other species. Published by Elsevier Ltd.

Wave aberrations in rhesus monkeys with vision-induced ametropias

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Ramamirtham, Ramkumar; Kee, Chea-su; Hung, Li-Fang; Qiao-Grider, Ying; Huang, Juan; Roorda, Austin; Smith, Earl L.

2007-01-01

The purpose of this study was to investigate the relationship between refractive errors and high-order aberrations in infant rhesus monkeys. Specifically, we compared the monochromatic wave aberrations measured with a Shack-Hartman wavefront sensor between normal monkeys and monkeys with vision-induced refractive errors. Shortly after birth, both normal monkeys and treated monkeys reared with optically induced defocus or form deprivation showed a decrease in the magnitude of high-order aberrations with age. However, the decrease in aberrations was typically smaller in the treated animals. Thus, at the end of the lens-rearing period, higher than normal amounts of aberrations were observed in treated eyes, both hyperopic and myopic eyes and treated eyes that developed astigmatism, but not spherical ametropias. The total RMS wavefront error increased with the degree of spherical refractive error, but was not correlated with the degree of astigmatism. Both myopic and hyperopic treated eyes showed elevated amounts of coma and trefoil and the degree of trefoil increased with the degree of spherical ametropia. Myopic eyes also exhibited a much higher prevalence of positive spherical aberration than normal or treated hyperopic eyes. Following the onset of unrestricted vision, the amount of high-order aberrations decreased in the treated monkeys that also recovered from the experimentally induced refractive errors. Our results demonstrate that high-order aberrations are influenced by visual experience in young primates and that the increase in high-order aberrations in our treated monkeys appears to be an optical byproduct of the vision-induced alterations in ocular growth that underlie changes in refractive error. The results from our study suggest that the higher amounts of wave aberrations observed in ametropic humans are likely to be a consequence, rather than a cause, of abnormal refractive development. PMID:17825347

Safety study of the Bio-10-SAD Bern strain of the rabies virus on the rhesus macaque monkey species

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Vladimír Vrzal

2013-01-01

Full Text Available Based on a WHO recommendation, residual pathogenicity of the Bio-10-SAD Bern rabies virus strain (component of the Lysvulpen por. ad us. vet. vaccine was tested on rhesus macaque monkeys. Each of the ten monkeys, females, two years old, was administered orally 2 ml × 109 TCID50 of the Bio-10-SAD Bern rabies strain. The animals were monitored for 90 days. Subsequently, the animals were sacrificed and their brains were examined for presence of the vaccination rabies virus by the immunofluorescence and PCR methods. The occurrence of anti-rabies antibodies prior to and following administration of the vaccination rabies virus was also evaluated. No clinical signs of rabies were observed nor did any of the animals die of rabies following application of the virus. No rabies was detected in the study animals by post mortem examination. All of the 10 animals developed anti-rabies antibodies during the 90 days following administration of the rabies virus. It can be concluded, that Bio-10-SAD Bern virus administered at a dose equal to the tenfold maximum dose specified for field uses is safe to monkeys of the rhesus macaque species. This study is the first of its type performed in rhesus macaque monkey species.

Effects of anesthesia upon 18F-FDG uptake in rhesus monkey brains

International Nuclear Information System (INIS)

Itoh, Takashi; Wakahara, Shunichi; Nakano, Takayuki; Suzuki, Kazutoshi; Kobayashi, Kaoru; Inoue, Osamu

2005-01-01

The kinetics of 18 F-fluorodeoxyglucose ( 18 F-FDG) in the monkey brain were monitored, and comparisons were made between the conscious state and when under ketamine and pentobarbital anesthesia. Rhesus monkeys were intravenously injected with 18 F-FDG and followed by 60 min of PET scanning. In the conscious state, the 18 F-FDG concentration reached a plateau 5 min after intravenous injection. Under ketamine anesthesia, the 18 F-FDG concentration gradually increased with time in all monitored regions. At 60 min after injection, the concentration in the striatum was about 3.2 times greater than that in the conscious state, and about 4.5 times greater in the cerebral cortex. Under pentobarbital anesthesia, the 18 F-FDG concentration in the occipital cortex was slightly lower. These findings demonstrate that 18 F-FDG concentration in the monkey brain is significantly affected by anesthesia. The results also imply the existence of a short-term regulation mechanism for hexokinase activity in intact monkey brain. (author)

Structural differences among serum IgA proteins of chimpanzee, rhesus monkey and rat origin

NARCIS (Netherlands)

Endo, T.; Radl, J.; Mestecky, J.

1997-01-01

Asparagine-linked sugar chains were quantitatively released from chimpanzee, Rhesus monkey and rat IgA proteins as oligosaccharides by hydrazinolysis, converted to radioactive oligosaccharides by reduction with NaB3H4, and separated into neutral and two acidic fractions by paper electrophoresis. The

Development of a rectal sexually transmitted infection (STI) Model in Rhesus macaques using Chlamydia trachomatis serovars E and L2.

Science.gov (United States)

Henning, Tara R; Morris, Monica; Ellis, Shanon; Kelley, Kristen; Phillips, Christi; Ritter, Jana; Jones, Tara; Nachamkin, Eli; Chen, Cheng Y; Hong, Jaeyoung; Kang, Joseph; Patton, Dorothy; McNicholl, Janet; Papp, John; Kersh, Ellen N

2017-10-01

Rectal STI coinfection models enhance the understanding of rectal HIV transmission risk factors. Rhesus macaques (n=9) were exposed to one of three rectal Chlamydia trachomatis (CT) challenges: C. trachomatis L 2 (CT-L 2 ); C. trachomatis serovar E (CT-E), followed by CT-L 2 ; or CT-E, treatment/clearance, then CT-L 2 . Infections were monitored by PCR. Weekly blood and rectal secretion/lavage samples were collected for cytokine analyzes and/or epithelial sloughing, occult, and overt blood determinations. Chlamydial infections were successfully established in each animal, with varying degrees of persistence. Mucosal IL-1beta was upregulated in animals consecutively infected with CT-E then CT-L 2 (P=.05). Epithelial sloughing was also significantly increased post-infection in this group (P=.0003). This study demonstrates successful rectal infection of rhesus macaques with CT-E and CT-L 2 and describes measures of assessing rectal inflammation and pathology. Different infection strategies yield varying inflammatory and pathologic outcomes, providing well-described models for future SIV/SHIV susceptibility studies. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Metabolism of lead-210 in juvenile and adult rhesus monkeys (Macaca mulatta)

International Nuclear Information System (INIS)

Pounds, J.G.; Marlar, R.J.; Allen, J.R.

1978-01-01

Experiments were conducted measuring the gastrointestinal absorption and elimination of a single dose of lead-210 acetate in infant and adult rhesus monkeys. Urinary and fecal excretion of absorbed lead was followed for 23 days. Infant monkeys eliminated less and absorbed more orally administered lead. Adult animals excreted more absorbed lead in feces, while urinary excretion between adults and infants was similar. Increased absorption of administered lead and reduced fecal excretion of absorbed lead resulted in significantly greater body burden of lead-210 in infant animals. Blood lead values were increased in the infant animals, and were inversely correlated with body burden and percent absorption of ingested lead

Is radiation-induced ovarian failure in rhesus monkeys preventable by luteinizing hormone-releasing hormone agonists?: Preliminary observations

International Nuclear Information System (INIS)

Ataya, K.; Pydyn, E.; Ramahi-Ataya

1995-01-01

With the advent of cancer therapy, increasing numbers of cancer patients are achieving long term survival. Impaired ovarian function after radiation therapy has been reported in several studies. Some investigators have suggested that luteinizing hormone-releasing hormone agonists (LHRHa) can prevent radiation-induced ovarian injury in rodents. Adult female rhesus monkeys were given either vehicle or Leuprolide acetate before, during, and after radiation. Radiation was given in a dose of 200 rads/day for a total of 4000 rads to the ovaries. Frequent serum samples were assayed for estradiol (E 2 ) and FSH. Ovariectomy was performed later. Ovaries were processed and serially sectioned. Follicle count and size distribution were determined. Shortly after radiation started, E 2 dropped to low levels, at which it remained, whereas serum FSH level, which was low before radiation, rose soon after starting radiation. In monkeys treated with a combination of LHRHa and radiation, FSH started rising soon after the LHRHa-loaded minipump was removed (after the end of radiation). Serum E 2 increased after the end of LHRHa treatment in the non-irradiated monkey, but not in the irradiated monkey. Follicle counts were not preserved in the LHRHa-treated monkeys that received radiation. The data demonstrated no protective effect of LHRHa treatment against radiation-induced ovarian injury in this rhesus monkey model. 58 refs., 2 figs., 1 tab

Sterile protection against Plasmodium knowlesi in rhesus monkeys from a malaria vaccine: comparison of heterologous prime boost strategies.

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George Jiang

Full Text Available Using newer vaccine platforms which have been effective against malaria in rodent models, we tested five immunization regimens against Plasmodium knowlesi in rhesus monkeys. All vaccines included the same four P. knowlesi antigens: the pre-erythrocytic antigens CSP, SSP2, and erythrocytic antigens AMA1, MSP1. We used four vaccine platforms for prime or boost vaccinations: plasmids (DNA, alphavirus replicons (VRP, attenuated adenovirus serotype 5 (Ad, or attenuated poxvirus (Pox. These four platforms combined to produce five different prime/boost vaccine regimens: Pox alone, VRP/Pox, VRP/Ad, Ad/Pox, and DNA/Pox. Five rhesus monkeys were immunized with each regimen, and five Control monkeys received a mock vaccination. The time to complete vaccinations was 420 days. All monkeys were challenged twice with 100 P. knowlesi sporozoites given IV. The first challenge was given 12 days after the last vaccination, and the monkeys receiving the DNA/Pox vaccine were the best protected, with 3/5 monkeys sterilely protected and 1/5 monkeys that self-cured its parasitemia. There was no protection in monkeys that received Pox malaria vaccine alone without previous priming. The second sporozoite challenge was given 4 months after the first. All 4 monkeys that were protected in the first challenge developed malaria in the second challenge. DNA, VRP and Ad5 vaccines all primed monkeys for strong immune responses after the Pox boost. We discuss the high level but short duration of protection in this experiment and the possible benefits of the long interval between prime and boost.

Two processes support visual recognition memory in rhesus monkeys.

Science.gov (United States)

Guderian, Sebastian; Brigham, Danielle; Mishkin, Mortimer

2011-11-29

A large body of evidence in humans suggests that recognition memory can be supported by both recollection and familiarity. Recollection-based recognition is characterized by the retrieval of contextual information about the episode in which an item was previously encountered, whereas familiarity-based recognition is characterized instead by knowledge only that the item had been encountered previously in the absence of any context. To date, it is unknown whether monkeys rely on similar mnemonic processes to perform recognition memory tasks. Here, we present evidence from the analysis of receiver operating characteristics, suggesting that visual recognition memory in rhesus monkeys also can be supported by two separate processes and that these processes have features considered to be characteristic of recollection and familiarity. Thus, the present study provides converging evidence across species for a dual process model of recognition memory and opens up the possibility of studying the neural mechanisms of recognition memory in nonhuman primates on tasks that are highly similar to the ones used in humans.

Lethal canine distemper virus outbreak in cynomolgus monkeys in Japan in 2008.

Science.gov (United States)

Sakai, Kouji; Nagata, Noriyo; Ami, Yasushi; Seki, Fumio; Suzaki, Yuriko; Iwata-Yoshikawa, Naoko; Suzuki, Tadaki; Fukushi, Shuetsu; Mizutani, Tetsuya; Yoshikawa, Tomoki; Otsuki, Noriyuki; Kurane, Ichiro; Komase, Katsuhiro; Yamaguchi, Ryoji; Hasegawa, Hideki; Saijo, Masayuki; Takeda, Makoto; Morikawa, Shigeru

2013-01-01

Canine distemper virus (CDV) has recently expanded its host range to nonhuman primates. A large CDV outbreak occurred in rhesus monkeys at a breeding farm in Guangxi Province, China, in 2006, followed by another outbreak in rhesus monkeys at an animal center in Beijing in 2008. In 2008 in Japan, a CDV outbreak also occurred in cynomolgus monkeys imported from China. In that outbreak, 46 monkeys died from severe pneumonia during a quarantine period. A CDV strain (CYN07-dV) was isolated in Vero cells expressing dog signaling lymphocyte activation molecule (SLAM). Phylogenic analysis showed that CYN07-dV was closely related to the recent CDV outbreaks in China, suggesting continuing chains of CDV infection in monkeys. In vitro, CYN07-dV uses macaca SLAM and macaca nectin4 as receptors as efficiently as dog SLAM and dog nectin4, respectively. CYN07-dV showed high virulence in experimentally infected cynomolgus monkeys and excreted progeny viruses in oral fluid and feces. These data revealed that some of the CDV strains, like CYN07-dV, have the potential to cause acute systemic infection in monkeys.

Differentiation and characterization of rhesus monkey atrial and ventricular cardiomyocytes from induced pluripotent stem cells.

Science.gov (United States)

Zhang, Xiaoqian; Cao, Henghua; Bai, Shuyun; Huo, Weibang; Ma, Yue

2017-04-01

The combination of non-human primate animals and their induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs) provides not only transplantation models for cell-based therapy of heart diseases, but also opportunities for heart-related drug research on both cellular and animal levels. However, the subtypes and electrophysiology properties of non-human primate iPSC-CMs hadn't been detailed characterized. In this study, we generated rhesus monkey induced pluripotent stem cells (riPSCs), and efficiently differentiated them into ventricular or atrial cardiomyocytes by modulating retinoic acid (RA) pathways. Our results revealed that the electrophysiological characteristics and response to canonical drugs of riPSC-CMs were similar with those of human pluripotent stem cell derived CMs. Therefore, rhesus monkeys and their iPSC-CMs provide a powerful and practicable system for heart related biomedical research. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Nalfurafine hydrochloride, a selective κ opioid receptor agonist, has no reinforcing effect on intravenous self-administration in rhesus monkeys

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Kaoru Nakao

2016-01-01

Full Text Available Nalfurafine hydrochloride [(E-N-[17-(cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxymorphinan-6β-yl]-3-(furan-3-yl-N-methylprop-2-enamide monohydrochloride; nalfurafine] is used in Japan as an antipruritic for the treatment of intractable pruritus in patients undergoing hemodialysis or with chronic liver disease. It is a potent and selective agonist at the κ opioid receptor, but also has weak and partial agonist activity at μ opioid receptors. Opioids, especially those acting at μ receptors, carry a risk of abuse. This is an important factor in the consideration of therapeutic risk vs. benefit in clinical use and the potential for misuse as a public health problem. It is therefore necessary to carefully evaluate the reinforcing effects of nalfurafine. To this end, we investigated intravenous self-administration of nalfurafine in rhesus monkeys. The number of self-administration of nalfurafine at doses of 0.0625, 0.125 and 0.25 μg/kg/infusion was not higher than that of saline in rhesus monkeys that frequently self-administered pentazocine (0.25 mg/kg/infusion. These results indicate that nalfurafine has no reinforcing effect in rhesus monkeys in the intravenous self-administration paradigm.

Radiographic Incidence of Spinal Osteopathologies in Captive Rhesus Monkeys (Macaca mulatta)

OpenAIRE

Hernández-Godínez, Braulio; Ibáñez-Contreras, Alejandra; Perdigón-Castañeda, Gerardo; Galván-Montaño, Alfonso; de Oca, Guadalupe García-Montes; Zapata-Valdez, Carinthia; Tena-Betancourt, Eduardo

2010-01-01

Degenerative spinal disease is a leading cause of chronic disability both in humans and animals. Although widely seen as a normal occurrence of aging, degenerative spinal disease can be caused by various genetic, iatrogenic, inflammatory, and congenital factors. The objective of this study was to characterize the degenerative spine-related diseases and the age at onset in a random subpopulation of 20 captive rhesus monkeys (Macaca mulatta; male, 13; female, 7; age: range, 4 to 27 y; median, 1...

Variability of bio-clinical parameters in Chinese-origin Rhesus macaques infected with simian immunodeficiency virus: a nonhuman primate AIDS model.

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Song Chen

Full Text Available BACKGROUND: Although Chinese-origin Rhesus macaques (Ch RhMs infected with simian immunodeficiency virus (SIV have been used for many years to evaluate the efficacy of AIDS vaccines and therapeutics, the bio-clinical variability of such a nonhuman primate AIDS model was so far not established. METHODOLOGY/PRINCIPAL FINDINGS: By randomizing 150 (78 male and 72 female Ch RhMs with diverse MHC class I alleles into 3 groups (50 animals per group challenged with intrarectal (i.r. SIVmac239, intravenous (i.v. SIVmac239, or i.v. SIVmac251, we evaluated variability in bio-clinical endpoints for 118 weeks. All SIV-challenged Ch RhMs became seropositive for SIV during 1-2 weeks. Plasma viral load (VL peaked at weeks 1-2 and then declined to set-point levels as from week 5. The set-point VL was 30 fold higher in SIVmac239 (i.r. or i.v.-infected than in SIVmac251 (i.v.-infected animals. This difference in plasma VL increased overtime (>100 fold as from week 68. The rates of progression to AIDS or death were more rapid in SIVmac239 (i.r. or i.v.-infected than in SIVmac251 (i.v.-infected animals. No significant difference in bio-clinical endpoints was observed in animals challenged with i.r. or i.v. SIVmac239. The variability (standard deviation in peak/set-point VL was nearly one-half lower in animals infected with SIVmac239 (i.r. or i.v. than in those infected with SIVmac251 (i.v., allowing that the same treatment-related difference can be detected with one-half fewer animals using SIVmac239 than using SIVmac251. CONCLUSION/SIGNIFICANCE: These results provide solid estimates of variability in bio-clinical endpoints needed when designing studies using the Ch RhM SIV model and contribute to the improving quality and standardization of preclinical studies.

Persistent Low-Level Replication of SIVΔnef Drives Maturation of Antibody and CD8 T Cell Responses to Induce Protective Immunity against Vaginal SIV Infection.

Science.gov (United States)

Adnan, Sama; Reeves, R Keith; Gillis, Jacqueline; Wong, Fay E; Yu, Yi; Camp, Jeremy V; Li, Qingsheng; Connole, Michelle; Li, Yuan; Piatak, Michael; Lifson, Jeffrey D; Li, Wenjun; Keele, Brandon F; Kozlowski, Pamela A; Desrosiers, Ronald C; Haase, Ashley T; Johnson, R Paul

2016-12-01

Defining the correlates of immune protection conferred by SIVΔnef, the most effective vaccine against SIV challenge, could enable the design of a protective vaccine against HIV infection. Here we provide a comprehensive assessment of immune responses that protect against SIV infection through detailed analyses of cellular and humoral immune responses in the blood and tissues of rhesus macaques vaccinated with SIVΔnef and then vaginally challenged with wild-type SIV. Despite the presence of robust cellular immune responses, animals at 5 weeks after vaccination displayed only transient viral suppression of challenge virus, whereas all macaques challenged at weeks 20 and 40 post-SIVΔnef vaccination were protected, as defined by either apparent sterile protection or significant suppression of viremia in infected animals. Multiple parameters of CD8 T cell function temporally correlated with maturation of protection, including polyfunctionality, phenotypic differentiation, and redistribution to gut and lymphoid tissues. Importantly, we also demonstrate the induction of a tissue-resident memory population of SIV-specific CD8 T cells in the vaginal mucosa, which was dependent on ongoing low-level antigenic stimulation. Moreover, we show that vaginal and serum antibody titers inversely correlated with post-challenge peak viral load, and we correlate the accumulation and affinity maturation of the antibody response to the duration of the vaccination period as well as to the SIVΔnef antigenic load. In conclusion, maturation of SIVΔnef-induced CD8 T cell and antibody responses, both propelled by viral persistence in the gut mucosa and secondary lymphoid tissues, results in protective immune responses that are able to interrupt viral transmission at mucosal portals of entry as well as potential sites of viral dissemination.

Natural and cross-inducible anti-SIV antibodies in Mauritian cynomolgus macaques.

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Hongzhao Li

Full Text Available Cynomolgus macaques are an increasingly important nonhuman primate model for HIV vaccine research. SIV-free animals without pre-existing anti-SIV immune responses are generally needed to evaluate the effect of vaccine-induced immune responses against the vaccine epitopes. Here, in order to select such animals for vaccine studies, we screened 108 naïve female Mauritian cynomolgus macaques for natural (baseline antibodies to SIV antigens using a Bio-Plex multiplex system. The antigens included twelve 20mer peptides overlapping the twelve SIV protease cleavage sites (-10/+10, respectively (PCS peptides, and three non-PCS Gag or Env peptides. Natural antibodies to SIV antigens were detected in subsets of monkeys. The antibody reactivity to SIV was further confirmed by Western blot using purified recombinant SIV Gag and Env proteins. As expected, the immunization of monkeys with PCS antigens elicited anti-PCS antibodies. However, unexpectedly, antibodies to non-PCS peptides were also induced, as shown by both Bio-Plex and Western blot analyses, while the non-PCS peptides do not share sequence homology with PCS peptides. The presence of natural and vaccine cross-inducible SIV antibodies in Mauritian cynomolgus macaques should be considered in animal selection, experimental design and result interpretation, for their best use in HIV vaccine research.

Diet choice, cortisol reactivity, and emotional feeding in socially housed rhesus monkeys

OpenAIRE

Arce, Marilyn; Michopoulos, Vasiliki; Shepard, Kathryn N.; Ha, Quynh-Chau; Wilson, Mark E.

2010-01-01

Chronic psychosocial stress produces an array of adverse health consequences that are highly comorbid, including emotional eating, affective disorders, and metabolic syndrome. The consumption of high caloric diets (HCD) is thought to provide comfort in the face of unrelenting psychosocial stress. Using social subordination in female rhesus monkeys as a model of continual exposure to daily stressors in women, we tested the hypothesis that subordinate females would consume significantly more ca...

Pathobiological and Behavioral Effects of Lead Intoxication in the Infant Rhesus Monkey

Science.gov (United States)

Allen, J. R.; McWey, P. J.; Suomi, S. J.

1974-01-01

When infant rhesus monkeys were exposed to lead via the addition of lead acetate (0.5–9 mg/kg body weight) to their formula or by the consumption of lead particles from lead-based surrogate mothers, they developed symptoms of lead intoxication within 6 weeks. Seizures, muscular tremors, and altered social interaction were the predominant changes. Visual impairment was also apparent in the more severely affected animals. In the animals showing obvious symptoms lead levels varied between 300 to 500 μg/100 ml of blood. Even in those animals having blood lead levels below 100 μg, hyperactivity and insomnia were observed. When the exposure to lead was eliminated, seizures subsided and visual impairment was reduced; however, the abnormal social interaction persisted. These animals also experienced a gradual decline in hematocrit and hemoglobin values during the period of examination. Liver and kidney biopsies obtained from these lead-exposed animals revealed characteristic intranuclear inclusions. When adolescent and adult monkeys were exposed to doses of lead acetate similar to those employed in the infant experiments, lead levels in excess of 200 μg/100 ml of blood were recorded. However, there were no obvious behavioral abnormalities observed. There were, however, numerous lead inclusion bodies in kidney biopsy specimens from these animals. These data suggest that, like man, the infant nonhuman primate is much more susceptible to lead intoxication than is the adult. The clinical and behavioral changes recorded in these infant rhesus monkeys suggest their use as an experimental model to evaluate lead intoxication. ImagesFIGURE 6. PMID:4208658

Control of SIV infection and subsequent induction of pandemic H1N1 immunity in rhesus macaques using an Ad5 [E1-, E2b-] vector platform.

Science.gov (United States)

Gabitzsch, Elizabeth S; Balint-Junior, Joseph P; Xu, Younong; Balcaitis, Stephanie; Sanders-Beer, Brigitte; Karl, Julie; Weinhold, Kent J; Paessler, Slobodan; Jones, Frank R

2012-11-26

Anti-vector immunity mitigates immune responses induced by recombinant adenovirus vector vaccines, limiting their prime-boost capabilities. We have developed a novel gene delivery and expression platform (Ad5 [E1-, E2b-]) that induces immune responses despite pre-existing and/or developed concomitant Ad5 immunity. In the present study, we evaluated if this new Ad5 platform could overcome the adverse condition of pre-existing Ad5 immunity to induce effective immune responses in prime-boost immunization regimens against two different infectious diseases in the same animal. Ad5 immune rhesus macaques (RM) were immunized multiple times with the Ad5 [E1-, E2b-] platform expressing antigens from simian immunodeficiency virus (SIV). Immunized RM developed cell-mediated immunity against SIV antigens Gag, Pol, Nef and Env as well as antibody against Env. Vaccinated and vector control RMs were challenged intra-rectally with homologous SIVmac239. During a 7-week follow-up, there was perturbation of SIV load in some immunized RM. At 7 weeks post-challenge, eight immunized animals (53%) did not have detectable SIV, compared to two RM controls (13%) (Pnow hyper immune to Ad5, were then vaccinated with the same Ad5 [E1-, E2b-] platform expressing H1N1 influenza hemagglutinin (HA). Thirty days post Ad5 [E1-, E2b-]-HA vaccination, significant levels of influenza neutralizing antibody were induced in all animals that increased after an Ad5 [E1-, E2b-]-HA homologous boost. These data demonstrate the versatility of this new vector platform to immunize against two separate disease targets in the same animal despite the presence of immunity against the delivery platform, permitting homologous repeat immunizations with an Ad5 gene delivery platform. Copyright © 2012 Elsevier Ltd. All rights reserved.

Evidence for a partial deficiency of the LDL (apo B,E) receptor within a family of rhesus monkeys with a spontaneous hypercholesterolemia

International Nuclear Information System (INIS)

Scanu, A.M.; Khalil, A.; Tidore, M.; Kaiser, M.; Pfaffinger, D.; Carey, D.; Dawson, G.

1987-01-01

Spontaneous hypercholesterolemia is rare among non-human primates. Through screening of a rhesus monkey colony they have identified a family in which 3 out of its 6 members have a persistent hypercholesterolemia on a cholesterol-free Purina Chow diet and are high responders to a dietary fat challenge. On a basal diet the 3 affected animals also exhibited high plasma levels of LDL and apoB. To shed light on the mechanism of the hypercholesterolemia they have grown in culture fibroblasts from skin biopsies obtained from all members of the rhesus monkey family and 12 control. Binding studies at 4 0 C and ligand blotting experiments using 125 I-LDL of either normolipidemic rhesus monkeys or human subjects have shown that the fibroblasts from the 3 monkeys with a spontaneous hypercholesterolemia have a significant reduction of the number of LDL receptor and to the same extent as fibroblasts derived from subjects with heterozygous FH studied at the same time. The data suggest that the spontaneous elevation of plasma cholesterol observed in the 3 family members is related, at least in part, to a defective uptake of LDL by the LDL receptor pathway

The Macaque Social Responsiveness Scale (mSRS: A Rapid Screening Tool for Assessing Variability in the Social Responsiveness of Rhesus Monkeys (Macaca mulatta.

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Eric J Feczko

Full Text Available Understanding the biological mechanisms underlying human neuropsychiatric disorders, such as autism spectrum disorder (ASD, has been hindered by the lack of a robust, translational animal model. Rhesus monkeys (Macaca mulatta display many of the same social behaviors that are affected in ASD, making them an excellent animal species in which to model social impairments. However, the social impairments associated with ASD may reflect extreme ends of a continuous distribution of traits. Thus, to validate the rhesus monkey as an animal model for studying social impairments that has strong translational relevance for ASD, researchers need an easily-implemented measurement tool that can quantify variation in social behavior dimensionally. The Social Responsiveness Scale (SRS is a 65-item survey that identifies both typical and atypical social behaviors in humans that covary with ASD symptom severity. A chimpanzee SRS has already been validated and the current study adapted this tool for use in the rhesus monkey (mSRS. Fifteen raters completed the mSRS for 105 rhesus monkeys living at the Yerkes National Primate Research Center. The mSRS scores showed a unimodal distribution with a positive skew that identified 6 statistical outliers. Inter-rater reliability was very strong, but only 17 of the 36 questions showed positive intra-item reliability. The results of an exploratory factor analysis identified 3 factors that explained over 60% of the variance, with 12 items significantly loading onto the primary factor. These items reflected behaviors associated with social avoidance, social anxiety or inflexibility and social confidence. These initial findings are encouraging and suggest that variability in the social responsiveness of rhesus monkeys can be quantified using the mSRS: a tool that has strong translational relevance for human disorders. With further modification, the mSRS may provide an promising new direction for research on the biological

Liver injury in rhesus monkeys subcutaneously injected with 2.3.7.8-tetrachlorodibenzo-p-dioxin

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Tatsumi, Korenaga; Fukusato, Toshio [Teikyo Univ., Tokyo (Japan). School of Medicine; Kubota, Shunichiro; Ohta, Mari [Tokyo Univ. (Japan); Asaoka, Kazuo [Kyoto Univ., Aichi (Japan); Murata, Nobuo [Teikyo Univ., Kawasaki (Japan). Mizonokuchi Hospital, School of Medicine; Nomizu, Motoyoshi [Hokkaido Univ., Sapporo (Japan); Arima, Akihiro [Shin Nippon Biomedical Laboratories, Ltd., Kagoshima (Japan)

2004-09-15

2.3.7.8-tetrachlorodibenzo-p-dioxin (TCDD) is the most toxic member of dioxins which are environmentally and biologically stable. Exposure to these compounds results in wide variety of effects including immunological dysfunction, tetragenecity and carcinogenesis. The liver is one of the central organs in which TCDD metabolized after absorption into the human and animal bodies. In experiments using rodents, TCDD accumulates and remains stable in the fatty tissues and liver for a long time. Kinetic profile of TCDD in our experiments using rhesus monkeys demonstrated the higher concentrations of TCDD in the fat, liver, and mammary gland. TCDD-induced liver injury in humans has been reported in Japan (PCB), Taiwan (PCB or PCDF), Italy (Sebeso, TCDD), and Vietnam (TCDD). Considerating the pronounced difference between species observed in some studies on non-human primates to assess effects of relatively low dose of TCDD, in the present study, liver injury in rhesus monkeys after a single subcutaneous administration of low dose of TCDD during pregnancy was investigated.

Real-time bioluminescence imaging of macroencapsulated fibroblasts reveals allograft protection in rhesus monkeys (Macaca mulatta).

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Tarantal, Alice F; Lee, C Chang I; Itkin-Ansari, Pamela

2009-07-15

Encapsulation of cells has the potential to eliminate the need for immunosuppression for cellular transplantation. Recently, the TheraCyte device was shown to provide long-term immunoprotection of murine islets in a mouse model of diabetes. In this report, translational studies were undertaken using skin fibroblasts from an unrelated rhesus monkey donor that were transduced with an HIV-1-derived lentiviral vector expressing firefly luciferase permitting the use of bioluminescence imaging (BLI) to monitor cell survival over time and in a noninvasive manner. Encapsulated cells were transplanted subcutaneously (n=2), or cells were injected without encapsulation (n=1) and outcomes compared. BLI was performed to monitor cell survival. The BLI signal from the encapsulated cells remained robust postinsertion and in one animal persisted for up to 1 year. In contrast, the control animal that received unencapsulated cells exhibited a complete loss of cell signal within 14 days. These data demonstrate that TheraCyte encapsulation of allogeneic cells provides robust immune protection in transplanted rhesus monkeys.

Single-cycle immunodeficiency viruses provide strategies for uncoupling in vivo expression levels from viral replicative capacity and for mimicking live-attenuated SIV vaccines

International Nuclear Information System (INIS)

Kuate, Seraphin; Stahl-Hennig, Christiane; Haaft, Peter ten; Heeney, Jonathan; Ueberla, Klaus

2003-01-01

To reduce the risks associated with live-attenuated immunodeficiency virus vaccines, single-cycle immunodeficiency viruses (SCIVs) were developed by primer complementation and production of the vaccine in the absence of vif in a vif-independent cell line. After a single intravenous injection of SCIVs into rhesus monkeys, peak viral RNA levels of 10 3 to 10 4 copies/ml plasma were observed, indicating efficient expression of SCIV in the vaccinee. After booster immunizations with SCIVs, SIV-specific humoral and cellular immune responses were observed. Although the vaccine doses used in this pilot study could not protect vaccinees from subsequent intravenous challenge with pathogenic SIVmac239, our results demonstrate that the novel SCIV approach allows us to uncouple in vivo expression levels from the viral replicative capacity facilitating the analysis of the relationship between viral expression levels or viral genes and immune responses induced by SIV

What interests them in the pictures?--differences in eye-tracking between rhesus monkeys and humans.

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Hu, Ying-Zhou; Jiang, Hui-Hui; Liu, Ci-Rong; Wang, Jian-Hong; Yu, Cheng-Yang; Carlson, Synnöve; Yang, Shang-Chuan; Saarinen, Veli-Matti; Rizak, Joshua D; Tian, Xiao-Guang; Tan, Hen; Chen, Zhu-Yue; Ma, Yuan-Ye; Hu, Xin-Tian

2013-10-01

Studies estimating eye movements have demonstrated that non-human primates have fixation patterns similar to humans at the first sight of a picture. In the current study, three sets of pictures containing monkeys, humans or both were presented to rhesus monkeys and humans. The eye movements on these pictures by the two species were recorded using a Tobii eye-tracking system. We found that monkeys paid more attention to the head and body in pictures containing monkeys, whereas both monkeys and humans paid more attention to the head in pictures containing humans. The humans always concentrated on the eyes and head in all the pictures, indicating the social role of facial cues in society. Although humans paid more attention to the hands than monkeys, both monkeys and humans were interested in the hands and what was being done with them in the pictures. This may suggest the importance and necessity of hands for survival. Finally, monkeys scored lower in eye-tracking when fixating on the pictures, as if they were less interested in looking at the screen than humans. The locations of fixation in monkeys may provide insight into the role of eye movements in an evolutionary context.

Rhesus Monkeys (Macaca Mulatta) Demonstrate Robust Memory for What and Where, but Not When, in an Open-Field Test of Memory

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Hampton, R.R.; Hampstead, B.M.; Murray, E.A.

2005-01-01

We adapted a paradigm developed by Clayton and Dickinson (1998), who demonstrated memory for what, where, and when in scrub jays, for use with rhesus monkeys. In the study phase of each trial, monkeys found a preferred and a less-preferred food reward in a trial-unique array of three locations in a large room. After 1h, monkeys returned to the…

Tissue-engineered rhesus monkey nerve grafts for the repair of long ulnar nerve defects: similar outcomes to autologous nerve grafts

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Chang-qing Jiang

2016-01-01

Full Text Available Acellular nerve allografts can help preserve normal nerve structure and extracellular matrix composition. These allografts have low immunogenicity and are more readily available than autologous nerves for the repair of long-segment peripheral nerve defects. In this study, we repaired a 40-mm ulnar nerve defect in rhesus monkeys with tissue-engineered peripheral nerve, and compared the outcome with that of autograft. The graft was prepared using a chemical extract from adult rhesus monkeys and seeded with allogeneic Schwann cells. Pathomorphology, electromyogram and immunohistochemistry findings revealed the absence of palmar erosion or ulcers, and that the morphology and elasticity of the hypothenar eminence were normal 5 months postoperatively. There were no significant differences in the mean peak compound muscle action potential, the mean nerve conduction velocity, or the number of neurofilaments between the experimental and control groups. However, outcome was significantly better in the experimental group than in the blank group. These findings suggest that chemically extracted allogeneic nerve seeded with autologous Schwann cells can repair 40-mm ulnar nerve defects in the rhesus monkey. The outcomes are similar to those obtained with autologous nerve graft.

Tissue-engineered rhesus monkey nerve gratfs for the repair of long ulnar nerve defects：similar outcomes to autologous nerve gratfs

Institute of Scientific and Technical Information of China (English)

Chang-qing Jiang; Jun Hu; Jian-ping Xiang; Jia-kai Zhu; Xiao-lin Liu; Peng Luo

2016-01-01

Acellular nerve allogratfs can help preserve normal nerve structure and extracellular matrix composition. These allogratfs have low immu-nogenicity and are more readily available than autologous nerves for the repair of long-segment peripheral nerve defects. In this study, we repaired a 40-mm ulnar nerve defect in rhesus monkeys with tissue-engineered peripheral nerve, and compared the outcome with that of autogratf. The gratf was prepared using a chemical extract from adult rhesus monkeys and seeded with allogeneic Schwann cells. Pathomo-rphology, electromyogram and immunohistochemistry ifndings revealed the absence of palmar erosion or ulcers, and that the morphology and elasticity of the hypothenar eminence were normal 5 months postoperatively. There were no signiifcant differences in the mean peak compound muscle action potential, the mean nerve conduction velocity, or the number of neuroiflaments between the experimental and control groups. However, outcome was signiifcantly better in the experimental group than in the blank group. These ifndings suggest that chemically extracted allogeneic nerve seeded with autologous Schwann cells can repair 40-mm ulnar nerve defects in the rhesus monkey. The outcomes are similar to those obtained with autologous nerve gratf.

Epithelium-innate immune cell axis in mucosal responses to SIV.

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Shang, L; Duan, L; Perkey, K E; Wietgrefe, S; Zupancic, M; Smith, A J; Southern, P J; Johnson, R P; Haase, A T

2017-03-01

In the SIV (simian immunodeficiency virus)-rhesus macaque model of HIV-1 (human immunodeficiency virus type I) transmission to women, one hallmark of the mucosal response to exposure to high doses of SIV is CD4 T-cell recruitment that fuels local virus expansion in early infection. In this study, we systematically analyzed the cellular events and chemoattractant profiles in cervical tissues that precede CD4 T-cell recruitment. We show that vaginal exposure to the SIV inoculum rapidly induces chemokine expression in cervical epithelium including CCL3, CCL20, and CXCL8. The chemokine expression is associated with early recruitment of macrophages and plasmacytoid dendritic cells that are co-clustered underneath the cervical epithelium. Production of chemokines CCL3 and CXCL8 by these cells in turn generates a chemokine gradient that is spatially correlated with the recruitment of CD4 T cells. We further show that the protection of SIVmac239Δnef vaccination against vaginal challenge is correlated with the absence of this epithelium-innate immune cell-CD4 T-cell axis response in the cervical mucosa. Our results reveal a critical role for cervical epithelium in initiating early mucosal responses to vaginal infection, highlight an important role for macrophages in target cell recruitment, and provide further evidence of a paradoxical dampening effect of a protective vaccine on these early mucosal responses.

Placental Transport of Zidovudine in the Rhesus Monkey

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King, Thomas S.; Henderson, George I.; Schenker, Steven; Schenken, Robert S.

1993-01-01

Objective: This study was undertaken to characterize the pharmacokinetics of zidovudine (ZDV) and ZDV-glucuronide (ZDVG) in the material and :fetal circulations of the rhesus monkey. Methods: Cannulas were placed in the maternal external jugular and the fetal internal jugular and carotid artery in 8 pregnant monkeys at .120–130 days gestation. ZDV (3.5 mg/kg) was administered to 5 monkeys and ZDVG (3.5 mg/kg) to 3 monkeys as single intravenous bolus infusions through the maternal catheter. Maternal and fetal blood , samples were collected every 20 min for the first 2 h and then every hour for the next 4 h. Maternal and fetal concentrations of ZDV and ZDVG were determined using high, performance liquid chromatography (HPLC) with ultraviolet (UV) detection. Results: In monkeys who received ZDV, the terminal half-life (T1/2) for ZDV was 37±15 and 33 ± 13 min in the maternal and fetal compartments, respectively. The apparent T1/2 for maternal ZDVG was 124 ± 44 and 142 ± 50 min in the maternal and fetal compartments, respectively. Peak levels of ZDV and ZDVG in the fetal compartment were reached 40 min after injection. The mean fetal/maternal concentration ratios for ZDV and ZDVG ranged from 0.20 ± 0.20 at 20 min to a maximum of 0.74 ± 1.0 at 120 min and from 0.28 ± 0.08 at 20 min to 1.4 ± 1.3 at 180 min, respectively. In monkeys who received ZDVG, the T1/2 for ZDWG in the maternal and fetal compartments was 47 ± 26 and 119 ± 164 min, respectively. ZDVG reached its peak in the fetal compartment at 60 min post-injection. The fetal/maternal rafio ranged from 0.08 ± 0.11 at 20 min to 4.2 ± 4.2 at 180 min post-injection. Conclusions: These data demonstrate that 1) ZDV and ZDVG rapidly cross the placenta to the fetal compartment, 2) ZDV crosses more rapidly than ZDVG, and 3) some metabolism of ZDV to ZDVG occurs in the fetal compartment. PMID:18475334

Pharmacokinetics and safety in rhesus monkeys of a monoclonal antibody-GDNF fusion protein for targeted blood-brain barrier delivery.

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Pardridge, William M; Boado, Ruben J

2009-10-01

Glial-derived neurotrophic factor (GDNF) is a potential therapy for stroke, Parkinson's disease, or drug addiction. However, GDNF does not cross the blood-brain barrier (BBB). GDNF is re-engineered as a fusion protein with a chimeric monoclonal antibody (MAb) to the human insulin receptor (HIR), which acts as a molecular Trojan horse to deliver the GDNF across the BBB. The pharmacokinetics (PK), toxicology, and safety pharmacology of the HIRMAb-GDNF fusion protein were investigated in Rhesus monkeys. The fusion protein was administered as an intravenous injection at doses up to 50 mg/kg over a 60 h period to 56 Rhesus monkeys. The plasma concentration of the HIRMAb-GDNF fusion protein was measured with a 2-site sandwich ELISA. No adverse events were observed in a 2-week terminal toxicology study, and no neuropathologic changes were observed. The PK analysis showed a linear relationship between plasma AUC and dose, a large systemic volume of distribution, as well as high clearance rates of 8-10 mL/kg/min. A no-observable-adverse-effect level is established in the Rhesus monkey for the acute administration of the HIRMAb-GDNF fusion protein. The fusion protein targeting the insulin receptor has a PK profile similar to a classical small molecule.

The Role of the Antiviral APOBEC3 Gene Family in Protecting Chimpanzees against Lentiviruses from Monkeys.

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Lucie Etienne

2015-09-01

Full Text Available Cross-species transmissions of viruses from animals to humans are at the origin of major human pathogenic viruses. While the role of ecological and epidemiological factors in the emergence of new pathogens is well documented, the importance of host factors is often unknown. Chimpanzees are the closest relatives of humans and the animal reservoir at the origin of the human AIDS pandemic. However, despite being regularly exposed to monkey lentiviruses through hunting, chimpanzees are naturally infected by only a single simian immunodeficiency virus, SIVcpz. Here, we asked why chimpanzees appear to be protected against the successful emergence of other SIVs. In particular, we investigated the role of the chimpanzee APOBEC3 genes in providing a barrier to infection by most monkey lentiviruses. We found that most SIV Vifs, including Vif from SIVwrc infecting western-red colobus, the chimpanzee's main monkey prey in West Africa, could not antagonize chimpanzee APOBEC3G. Moreover, chimpanzee APOBEC3D, as well as APOBEC3F and APOBEC3H, provided additional protection against SIV Vif antagonism. Consequently, lentiviral replication in primary chimpanzee CD4(+ T cells was dependent on the presence of a lentiviral vif gene that could antagonize chimpanzee APOBEC3s. Finally, by identifying and functionally characterizing several APOBEC3 gene polymorphisms in both common chimpanzees and bonobos, we found that these ape populations encode APOBEC3 proteins that are uniformly resistant to antagonism by monkey lentiviruses.

Ethograms indicate stable well-being during prolonged training phases in rhesus monkeys used in neurophysiological research.

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Hage, Steffen R; Ott, Torben; Eiselt, Anne-Kathrin; Jacob, Simon N; Nieder, Andreas

2014-01-01

Awake, behaving rhesus monkeys are widely used in neurophysiological research. Neural signals are typically measured from monkeys trained with operant conditioning techniques to perform a variety of behavioral tasks in exchange for rewards. Over the past years, monkeys' psychological well-being during experimentation has become an increasingly important concern. We suggest objective criteria to explore whether training sessions during which the monkeys work under controlled water intake over many days might affect their behavior. With that aim, we analyzed a broad range of species-specific behaviors over several months ('ethogram') and used these ethograms as a proxy for the monkeys' well-being. Our results show that monkeys' behavior during training sessions is unaffected by the duration of training-free days in-between. Independently of the number of training-free days (two or nine days) with ad libitum food and water supply, the monkeys were equally active and alert in their home group cages during training phases. This indicates that the monkeys were well habituated to prolonged working schedules and that their well-being was stably ensured during the training sessions.

Peer social interaction is facilitated in juvenile rhesus monkeys treated with fluoxetine.

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Golub, Mari S; Hogrefe, Casey E; Bulleri, Alicia M

2016-06-01

Fluoxetine improves social interactions in children with autism, social anxiety and social phobia. It is not known whether this effect is mediated directly or indirectly by correcting the underlying pathology. Genetics may also influence the drug effect. Polymorphisms of the MAOA (monoamine oxidase A) gene interact with fluoxetine to influence metabolic profiles in juvenile monkeys. Juvenile nonhuman primates provide an appropriate model for studying fluoxetine effects and drug*gene interactions in children. Male rhesus monkeys 1-3 years of age living in permanent social pairs were treated daily with a therapeutic dose of fluoxetine or vehicle (n = 16/group). Both members of each social pair were assigned to the same treatment group. They were observed for social interactions with their familiar cagemate over a 2-year dosing period. Subjects were genotyped for MAOA variable number of tandem repeats (VNTR) polymorphisms categorized for high or low transcription rates (hi-MAOA, low-MAOA). Fluoxetine-treated animals spent 30% more time in social interaction than vehicle controls. Fluoxetine significantly increased the duration of quiet interactions, the most common type of interaction, and also of immature sexual behavior typical of rhesus in this age group. Specific behaviors affected depended on MAOA genotype of the animal and its social partner. When given fluoxetine, hi-MOAO monkeys had more social invitation and initiation behaviors and low-MAOA subjects with low-MAOA partners had more grooming and an increased frequency of some facial and vocal expressive behaviors. Fluoxetine may facilitate social interaction in children independent of remediation of psychopathology. Common genetic variants may modify this effect. Copyright © 2016 Elsevier Ltd. All rights reserved.

Epigenetic mechanism underlying the development of polycystic ovary syndrome (PCOS-like phenotypes in prenatally androgenized rhesus monkeys.

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Ning Xu

Full Text Available The pathogenesis of polycystic ovary syndrome (PCOS is poorly understood. PCOS-like phenotypes are produced by prenatal androgenization (PA of female rhesus monkeys. We hypothesize that perturbation of the epigenome, through altered DNA methylation, is one of the mechanisms whereby PA reprograms monkeys to develop PCOS. Infant and adult visceral adipose tissues (VAT harvested from 15 PA and 10 control monkeys were studied. Bisulfite treated samples were subjected to genome-wide CpG methylation analysis, designed to simultaneously measure methylation levels at 27,578 CpG sites. Analysis was carried out using Bayesian Classification with Singular Value Decomposition (BCSVD, testing all probes simultaneously in a single test. Stringent criteria were then applied to filter out invalid probes due to sequence dissimilarities between human probes and monkey DNA, and then mapped to the rhesus genome. This yielded differentially methylated loci between PA and control monkeys, 163 in infant VAT, and 325 in adult VAT (BCSVD P<0.05. Among these two sets of genes, we identified several significant pathways, including the antiproliferative role of TOB in T cell signaling and transforming growth factor-β (TGF-β signaling. Our results suggest PA may modify DNA methylation patterns in both infant and adult VAT. This pilot study suggests that excess fetal androgen exposure in female nonhuman primates may predispose to PCOS via alteration of the epigenome, providing a novel avenue to understand PCOS in humans.

Persistent Low-Level Replication of SIVΔnef Drives Maturation of Antibody and CD8 T Cell Responses to Induce Protective Immunity against Vaginal SIV Infection.

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Sama Adnan

2016-12-01

Full Text Available Defining the correlates of immune protection conferred by SIVΔnef, the most effective vaccine against SIV challenge, could enable the design of a protective vaccine against HIV infection. Here we provide a comprehensive assessment of immune responses that protect against SIV infection through detailed analyses of cellular and humoral immune responses in the blood and tissues of rhesus macaques vaccinated with SIVΔnef and then vaginally challenged with wild-type SIV. Despite the presence of robust cellular immune responses, animals at 5 weeks after vaccination displayed only transient viral suppression of challenge virus, whereas all macaques challenged at weeks 20 and 40 post-SIVΔnef vaccination were protected, as defined by either apparent sterile protection or significant suppression of viremia in infected animals. Multiple parameters of CD8 T cell function temporally correlated with maturation of protection, including polyfunctionality, phenotypic differentiation, and redistribution to gut and lymphoid tissues. Importantly, we also demonstrate the induction of a tissue-resident memory population of SIV-specific CD8 T cells in the vaginal mucosa, which was dependent on ongoing low-level antigenic stimulation. Moreover, we show that vaginal and serum antibody titers inversely correlated with post-challenge peak viral load, and we correlate the accumulation and affinity maturation of the antibody response to the duration of the vaccination period as well as to the SIVΔnef antigenic load. In conclusion, maturation of SIVΔnef-induced CD8 T cell and antibody responses, both propelled by viral persistence in the gut mucosa and secondary lymphoid tissues, results in protective immune responses that are able to interrupt viral transmission at mucosal portals of entry as well as potential sites of viral dissemination.

Effects on executive function following damage to the prefrontal cortex in the rhesus monkey (Macaca mulatta).

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Moore, Tara L; Schettler, Stephen P; Killiany, Ronald J; Rosene, Douglas L; Moss, Mark B

2009-04-01

Executive function is a term used to describe the cognitive processes subserved by the prefrontal cortex (PFC). An extensive body of work has characterized the effects of damage to the PFC in nonhuman primates, but it has focused primarily on the capacity of recognition and working memory. One limitation in studies of the functional parcellation of the PFC has been the absence of tests that assess executive function or its functional components. The current study used an adaptation of the Wisconsin Card Sorting Test, a classic test of frontal lobe and executive function in humans, to assess the effects of bilateral lesions in the dorsolateral PFC on executive function in the rhesus monkey (Macaca mulatta). The authors used the category set-shifting task, which requires the monkey to establish a pattern of responding to a specific category (color or shape) based on reward contingency, maintain that pattern of responding, and then shift to responding to a different category when the reward contingency changes. Rhesus monkeys with lesions of the dorsolateral PFC were impaired in abstraction, establishing a response pattern to a specific category and maintaining and shifting that response pattern on the category set-shifting task. (c) 2009 APA, all rights reserved.

The migration of 111Indium-labelled polymorphonuclear leucocytes into the oral cavity in the rhesus monkey

International Nuclear Information System (INIS)

Scully, C.; Challacombe, S.J.

1979-01-01

The route of migration of polymorphonuclear leucocytes (PMNL) from blood to the oral cavity was examined in rhesus monkeys. PMNL were isolated from the peripheral blood of eleven rhesus monkeys by dextran sedimentation, radiolabelled with 111 Indium and administered intravenously. Sequential samples of crevicular fluid washings (CFW), mixed and parotid saliva and mucosal washings were taken after injection of the labelled PMNL and harvested on glass fibre discs. Highest numbers of labelled PMNL were detected in CFW. CEll-associated radioactivity was detected in CFW within 20 min of injection of labelled PMNL and reached a maximal level 1 hour after injection. PMNL were found in CFW from monkeys with clinically normal gingiva but the number of labelled PMNL in CFW increased with increasing gingival index. Significant number of PMNL migrated into mixed saliva within 30 min, and low numbers of PMNL were detected in mucosal washings and in parotid saliva after 30 min. The results indicate that the migration time of the PMNL from blood to the oral cavity is less than 30 min, irrespective of the gingival index, that the gingival crevice is the main route of entry of PMNL to the oral cavity and that the numbers of PMNL migrating to the crevice increase as the gingival index rises. (author)

Tissue-specific B-cell dysfunction and generalized memory B-cell loss during acute SIV infection.

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Sandrine Peruchon

Full Text Available BACKGROUND: Primary HIV-infected patients display severe and irreversible damage to different blood B-cell subsets which is not restored by highly efficient anti-retroviral therapy (HAART. Because longitudinal investigations of primary HIV-infection is limited by the availability of lymphoid organs, we studied the tissue-specific B-cell dysfunctions in acutely simian immunodeficiency virus (SIV mac251-infected Cynomolgus macaques. METHODS AND FINDINGS: Experiments were performed on three groups of macaques infected for 14, 21 or 28 days and on three groups of animals treated with HAART for two-weeks either initiated at 4 h, 7 or 14 days post-infection (p.i.. We have simultaneously compared changes in B-cell phenotypes and functions and tissue organization of B-cell areas in various lymphoid organs. We showed that SIV induced a steady decline in SIgG-expressing memory (SIgD(-CD27(+ B-cells in spleen and lymph nodes during the first 4 weeks of infection, concomitant to selective homing/sequestration of B-cells to the small intestine and spleen. SIV non-specific Ig production was transiently increased before D14p.i., whereas SIV-specific Ig production was only detectable after D14p.i., coinciding with the presence of CD8(+ T-cells and IgG-expressing plasma cells within germinal centres. Transient B-cell apoptosis on D14p.i. and commitment to terminal differentiation contributed to memory B-cell loss. HAART abrogated B-cell apoptosis, homing to the small intestine and SIV-specific Ig production but had minimal effect on early Ig production, increased B-cell proportions in spleen and loss of memory B-cells. Therefore, virus-B-cell interactions and SIV-induced inflammatory cytokines may differently contribute to early B-cell dysfunction and impaired SIV/HIV-specific antibody response. CONCLUSIONS: These data establish tissue-specific impairments in B-cell trafficking and functions and a generalized and steady memory B-cell loss in secondary lymphoid

Nonprogressing HIV-infected children share fundamental immunological features of nonpathogenic SIV infection

DEFF Research Database (Denmark)

Muenchhoff, Maximilian; Adland, Emily; Karimanzira, Owen

2016-01-01

nonprogressors. These children therefore express two cardinal immunological features of nonpathogenic SIV infection in sooty mangabeys-low immune activation despite high viremia and low CCR5 expression on long-lived central memory CD4 T cells-suggesting closer similarities with nonpathogenetic mechanisms evolved...

Pharmacokinetics of bisphenol A in neonatal and adult rhesus monkeys

International Nuclear Information System (INIS)

Doerge, Daniel R.; Twaddle, Nathan C.; Woodling, Kellie A.; Fisher, Jeffrey W.

2010-01-01

Bisphenol A (BPA) is a high-production volume industrial chemical used in the manufacture of polycarbonate plastic products and epoxy resin-based food can liners. The presence of BPA in urine of > 90% of Americans aged 6-60 is controversial because of the potential for endocrine disruption, particularly during perinatal development, as suggested by in vitro, experimental animal, and epidemiological studies. The current study used LC/MS/MS to measure serum pharmacokinetics of aglycone (active) and conjugated (inactive) BPA in adult and neonatal rhesus monkeys by oral (PND 5, 35, 70) and intravenous injection (PND 77) routes using d6-BPA to avoid sample contamination. The concentration-time profiles observed in adult monkeys following oral administration of 100 μg/kg bw were remarkably similar to those previously reported in human volunteers given a similar dose; moreover, minimal pharmacokinetic differences were observed between neonatal and adult monkeys for the receptor-active aglycone form of BPA. Circulating concentrations of BPA aglycone were quite low following oral administration (< 1% of total), which reflects the redundancy of active UDP-glucuronosyl transferase isoforms in both gut and liver. No age-related changes were seen in internal exposure metrics for aglycone BPA in monkeys, a result clearly different from developing rats where significant inverse age-related changes, based on immaturity of Phase II metabolism and renal excretion, were recently reported. These observations imply that any toxicological effect observed in rats from early postnatal exposures to BPA could over-predict those possible in primates of the same age, based on significantly higher internal exposures and overall immaturity at birth.

Selection of unrelated donors for bone marrow transplantation studied in rhesus monkeys

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Wagemaker, G.; Bekkum, D.W. van

Graft versus Host disease (GvHD) remains to be a severe limitation to a more general application of bone marrow transplantation. Clinically acceptable results are restricted to those potential recipients for which a major histocompatibility complex (MHC) identical sibling donor is available. At an average family size of 2 to 3 siblings, the frequency of such donors is not more than approximately 30%. This pre-clinical study in rhesus monkeys is directed at the selection of donors for recipients which lack an MHC identical sibling. (Auth.)

A novel protective MHC-I haplotype not associated with dominant Gag-specific CD8+ T-cell responses in SIVmac239 infection of Burmese rhesus macaques.

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Naofumi Takahashi

Full Text Available Several major histocompatibility complex class I (MHC-I alleles are associated with lower viral loads and slower disease progression in human immunodeficiency virus (HIV and simian immunodeficiency virus (SIV infections. Immune-correlates analyses in these MHC-I-related HIV/SIV controllers would lead to elucidation of the mechanism for viral control. Viral control associated with some protective MHC-I alleles is attributed to CD8+ T-cell responses targeting Gag epitopes. We have been trying to know the mechanism of SIV control in multiple groups of Burmese rhesus macaques sharing MHC-I genotypes at the haplotype level. Here, we found a protective MHC-I haplotype, 90-010-Id (D, which is not associated with dominant Gag-specific CD8+ T-cell responses. Viral loads in five D+ animals became significantly lower than those in our previous cohorts after 6 months. Most D+ animals showed predominant Nef-specific but not Gag-specific CD8+ T-cell responses after SIV challenge. Further analyses suggested two Nef-epitope-specific CD8+ T-cell responses exerting strong suppressive pressure on SIV replication. Another set of five D+ animals that received a prophylactic vaccine using a Gag-expressing Sendai virus vector showed significantly reduced viral loads compared to unvaccinated D+ animals at 3 months, suggesting rapid SIV control by Gag-specific CD8+ T-cell responses in addition to Nef-specific ones. These results present a pattern of SIV control with involvement of non-Gag antigen-specific CD8+ T-cell responses.

Mucinous gastric hyperplasia in a colony of rhesus monkeys (Macaca mulatta) induced by polychlorinated biphenyl (Aroclor 1254)

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Geistfeld, J.G.; Bond, M.G.; Bullock, B.C.; Varian, M.C.

1982-02-01

Since 1971, 45 of 259 male rhesus monkeys housed in a primate building have died of a chronic and progressive disease characterized by diarrhea, dehydration, weakness, gingivitis, emaciation, and alopecia. The principal necropsy finding in these monkeys, and in eight others killed for experimental purposes, was hypertrophic and hyperplastic mucinous gastropathy involving both the mucosa and submucosa. The toxic agent involved was identified as the polychlorinated biphenyl (PCB), Aroclor 1254. The suspected source of the toxic agent was a concrete sealer used during building construction.

The calcium endocrine system of adolescent rhesus monkeys and controls before and after spaceflight

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Arnaud, Sara B.; Navidi, Meena; Deftos, Leonard; Thierry-Palmer, Myrtle; Dotsenko, Rita; Bigbee, Allison; Grindeland, Richard E.

2002-01-01

The calcium endocrine system of nonhuman primates can be influenced by chairing for safety and the weightless environment of spaceflight. The serum of two rhesus monkeys flown on the Bion 11 mission was assayed pre- and postflight for vitamin D metabolites, parathyroid hormone, calcitonin, parameters of calcium homeostasis, cortisol, and indexes of renal function. Results were compared with the same measures from five monkeys before and after chairing for a flight simulation study. Concentrations of 1,25-dihydroxyvitamin D were 72% lower after the flight than before, and more than after chairing on the ground (57%, P endocrine system were similar to the effects of chairing on the ground, but were more pronounced. Reduced intestinal calcium absorption, losses in body weight, increases in cortisol, and higher postflight blood urea nitrogen were the changes in flight monkeys that distinguished them from the flight simulation study animals.

Innate Lymphoid Cells in HIV/SIV Infections.

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Shah, Spandan V; Manickam, Cordelia; Ram, Daniel R; Reeves, R Keith

2017-01-01

Over the past several years, new populations of innate lymphocytes have been described in mice and primates that are critical for mucosal homeostasis, microbial regulation, and immune defense. Generally conserved from mice to humans, innate lymphoid cells (ILC) have been divided primarily into three subpopulations based on phenotypic and functional repertoires: ILC1 bear similarities to natural killer cells; ILC2 have overlapping functions with TH2 cells; and ILC3 that share many functions with TH17/TH22 cells. ILC are specifically enriched at mucosal surfaces and are possibly one of the earliest responders during viral infections besides being involved in the homeostasis of gut-associated lymphoid tissue and maintenance of gut epithelial barrier integrity. Burgeoning evidence also suggests that there is an early and sustained abrogation of ILC function and numbers during HIV and pathogenic SIV infections, most notably ILC3 in the gastrointestinal tract, which leads to disruption of the mucosal barrier and dysregulation of the local immune system. A better understanding of the direct or indirect mechanisms of loss and dysfunction will be critical to immunotherapeutics aimed at restoring these cells. Herein, we review the current literature on ILC with a particular emphasis on ILC3 and their role(s) in mucosal immunology and the significance of disrupting the ILC niche during HIV and SIV infections.

Innate Lymphoid Cells in HIV/SIV Infections

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Spandan V. Shah

2017-12-01

Full Text Available Over the past several years, new populations of innate lymphocytes have been described in mice and primates that are critical for mucosal homeostasis, microbial regulation, and immune defense. Generally conserved from mice to humans, innate lymphoid cells (ILC have been divided primarily into three subpopulations based on phenotypic and functional repertoires: ILC1 bear similarities to natural killer cells; ILC2 have overlapping functions with TH2 cells; and ILC3 that share many functions with TH17/TH22 cells. ILC are specifically enriched at mucosal surfaces and are possibly one of the earliest responders during viral infections besides being involved in the homeostasis of gut-associated lymphoid tissue and maintenance of gut epithelial barrier integrity. Burgeoning evidence also suggests that there is an early and sustained abrogation of ILC function and numbers during HIV and pathogenic SIV infections, most notably ILC3 in the gastrointestinal tract, which leads to disruption of the mucosal barrier and dysregulation of the local immune system. A better understanding of the direct or indirect mechanisms of loss and dysfunction will be critical to immunotherapeutics aimed at restoring these cells. Herein, we review the current literature on ILC with a particular emphasis on ILC3 and their role(s in mucosal immunology and the significance of disrupting the ILC niche during HIV and SIV infections.

3B11-N, a monoclonal antibody against MERS-CoV, reduces lung pathology in rhesus monkeys following intratracheal inoculation of MERS-CoV Jordan-n3/2012

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Johnson, Reed F.; Bagci, Ulas; Keith, Lauren; Tang, Xianchun; Mollura, Daniel J.; Zeitlin, Larry; Qin, Jing; Huzella, Louis; Bartos, Christopher J.; Bohorova, Natasha; Bohorov, Ognian; Goodman, Charles; Kim, Do H.; Paulty, Michael H.; Velasco, Jesus; Whaley, Kevin J.; Johnson, Joshua C.; Pettitt, James; Ork, Britini L.; Solomon, Jeffrey

2016-01-01

Middle East Respiratory Syndrome Coronavirus (MERS-CoV) was identified in 2012 as the causative agent of a severe, lethal respiratory disease occurring across several countries in the Middle East. To date there have been over 1600 laboratory confirmed cases of MERS-CoV in 26 countries with a case fatality rate of 36%. Given the endemic region, it is possible that MERS-CoV could spread during the annual Hajj pilgrimage, necessitating countermeasure development. In this report, we describe the clinical and radiographic changes of rhesus monkeys following infection with 5×10"6 PFU MERS-CoV Jordan-n3/2012. Two groups of NHPs were treated with either a human anti-MERS monoclonal antibody 3B11-N or E410-N, an anti-HIV antibody. MERS-CoV Jordan-n3/2012 infection resulted in quantifiable changes by computed tomography, but limited other clinical signs of disease. 3B11-N treated subjects developed significantly reduced lung pathology when compared to infected, untreated subjects, indicating that this antibody may be a suitable MERS-CoV treatment. - Highlights: • MERS-CoV Jordan-n3/2012 challenge of rhesus monkeys results in a mild disease. • CT can be used to monitor disease progression to aid models of human disease. • Treatment with the human monoclonal antibody 3B11-N resulted in decreased disease.

3B11-N, a monoclonal antibody against MERS-CoV, reduces lung pathology in rhesus monkeys following intratracheal inoculation of MERS-CoV Jordan-n3/2012

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Johnson, Reed F., E-mail: johnsonreed@mail.nih.gov [Emerging Viral Pathogens Section National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, MD 21702 (United States); Bagci, Ulas [Center for Infectious Disease Imaging, National Institutes of Health Clinical Center, Bethesda MD 20892 (United States); Center for Research in Computer Vision (CRCV), Department of Electrics Electronics and Computer Science, University of Central Florida, Orlando, FL 32816, USA. (United States); Keith, Lauren [Integrated Research Facility, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, MD 21702 (United States); Tang, Xianchun [Department of Cancer Immunology & AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215 (United States); Mollura, Daniel J. [Center for Infectious Disease Imaging, National Institutes of Health Clinical Center, Bethesda MD 20892 (United States); Zeitlin, Larry [Mapp Biopharmaceutical, Inc., San Diego CA 92121 (United States); Qin, Jing [Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892 (United States); Huzella, Louis; Bartos, Christopher J. [Integrated Research Facility, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, MD 21702 (United States); Bohorova, Natasha; Bohorov, Ognian; Goodman, Charles; Kim, Do H.; Paulty, Michael H.; Velasco, Jesus; Whaley, Kevin J. [Mapp Biopharmaceutical, Inc., San Diego CA 92121 (United States); Johnson, Joshua C.; Pettitt, James; Ork, Britini L. [Integrated Research Facility, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, MD 21702 (United States); Solomon, Jeffrey [Clinical Research Directorate/Clinical Monitoring Research Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research,Frederick, MD 21702-USA. (United States); and others

2016-03-15

Middle East Respiratory Syndrome Coronavirus (MERS-CoV) was identified in 2012 as the causative agent of a severe, lethal respiratory disease occurring across several countries in the Middle East. To date there have been over 1600 laboratory confirmed cases of MERS-CoV in 26 countries with a case fatality rate of 36%. Given the endemic region, it is possible that MERS-CoV could spread during the annual Hajj pilgrimage, necessitating countermeasure development. In this report, we describe the clinical and radiographic changes of rhesus monkeys following infection with 5×10{sup 6} PFU MERS-CoV Jordan-n3/2012. Two groups of NHPs were treated with either a human anti-MERS monoclonal antibody 3B11-N or E410-N, an anti-HIV antibody. MERS-CoV Jordan-n3/2012 infection resulted in quantifiable changes by computed tomography, but limited other clinical signs of disease. 3B11-N treated subjects developed significantly reduced lung pathology when compared to infected, untreated subjects, indicating that this antibody may be a suitable MERS-CoV treatment. - Highlights: • MERS-CoV Jordan-n3/2012 challenge of rhesus monkeys results in a mild disease. • CT can be used to monitor disease progression to aid models of human disease. • Treatment with the human monoclonal antibody 3B11-N resulted in decreased disease.

Plasma disappearance, urine excretion, and tissue distribution of ribavirin in rats and rhesus monkeys

International Nuclear Information System (INIS)

Ferrara, E.A.; Oishi, J.S.; Wannemacher, R.W. Jr.; Stephen, E.L.

1981-01-01

Ribavirin has been shown to have broad-spectrum antiviral. To study its tissue distribution and disappearance rate, a single dose of 10 mg/kg which contained 10 microCi of [14C]ribavirin was injected intravenously into rhesus monkeys and intramuscularly into monkeys and rats. Except for peak plasma concentrations and the initial phases of the plasma disappearance and urine excretion curves, no significant difference was observed between plasma, tissue, or urine values for intramuscularly or intravenously injected monkeys. Plasma disappearance curves were triphasic; plasma concentrations of ribavirin were similar for both monkeys and rats. Rats excreted ribavirin in the urine more rapidly and to a greater extent (82% excreted in 24 h) than did monkeys (60% excreted in 72 h). In the rat, only 3% of the injected [14C]ribavirin was detected in expired CO2. Therefore, for both species, urine was the major route for the elimination of labeled ribavirin and its metabolites from the body. In monkeys, the amount of parent drug in blood cells increased through 48 h and remained stable for 72 h, whereas in rats, ribavirin decreased at a rate similar to the plasma disappearance curve. Concentrations of ribavirin at 8 h were consistently higher in monkeys than in rats for all tissues except the brain. Thus, these differences in blood cellular components and organ content and in urine excretion suggested that there was greater tissue retention of ribavirin in monkeys than in rats

Role of complement and antibodies in controlling infection with pathogenic simian immunodeficiency virus (SIV in macaques vaccinated with replication-deficient viral vectors

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Strasak Alexander

2009-06-01

Full Text Available Abstract Background We investigated the interplay between complement and antibodies upon priming with single-cycle replicating viral vectors (SCIV encoding SIV antigens combined with Adeno5-SIV or SCIV pseudotyped with murine leukemia virus envelope boosting strategies. The vaccine was applied via spray-immunization to the tonsils of rhesus macaques and compared with systemic regimens. Results Independent of the application regimen or route, viral loads were significantly reduced after challenge with SIVmac239 (p Conclusion The heterologous prime-boost strategy with replication-deficient viral vectors administered exclusively via the tonsils did not induce any neutralizing antibodies before challenge. However, after challenge, comparable SIV-specific humoral immune responses were observed in all vaccinated animals. Immunization with single cycle immunodeficiency viruses mounts humoral immune responses comparable to live-attenuated immunodeficiency virus vaccines.

HTRA3 expression in non-pregnant rhesus monkey ovary and endometrium, and at the maternal-fetal interface during early pregnancy

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Findlay Jock K

2008-06-01

Full Text Available Abstract Background HTRA3 is a recently identified member of the mammalian serine protease family HTRA (high temperature requirement factor A. In both the rodent and the human HTRA3 is transcribed into two mRNA species (long and short through alternative splicing. We have previously shown that HTRA3 is expressed in the mature rat ovary and may be involved in folliculogenesis and luteinisation. HTRA3 is also upregulated during mouse and human placental development. The current study investigated whether HTRA3 is also localised in the primate ovary (rhesus monkey n = 7. In addition, we examined the non-pregnant rhesus monkey endometrium (n = 4 and maternal-fetal interface during early pregnancy (n = 5 to further investigate expression of HTRA3 in primate endometrium and placentation. Methods HTRA3 mRNA levels in several rhesus monkey tissues was determined by semiquantitative RT-PCR. Protein expression and localisation of HTRA3 was determined by immunohistochemistry. Results Long and short forms of HTRA3 mRNA were detected in the ovary, aorta, bladder, small intestine, skeletal muscle, heart and uterus but not the liver nor the kidney. HTRA3 protein was immunolocalised to the oocyte of all follicular stages in the rhesus monkey ovary. Protein expression in mural and cumulus granulosa cells of late secondary follicles increased significantly compared to granulosa cells of primordial, primary and secondary follicles. Mural and cumulus granulosa cells of antral follicles also showed a significant increase in expression. Staining intensity was higher in the granulosa-lutein cells compared to the theca-lutein cells of corpora lutea (n = 3. In the non-pregnant monkey endometrium, HTRA3 was detected in the glandular epithelium. The basalis endometrial glands showed higher staining intensity than functionalis endometrial glands. During early pregnancy, strong staining for HTRA3 protein was seen in both maternal decidual cells and glands. Conclusion We

Comparative Metabolism Study of Five Protoberberine Alkaloids in Liver Microsomes from Rat, Rhesus Monkey, and Human.

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Li, Yan; Zhou, Yanyan; Si, Nan; Han, Lingyu; Ren, Wei; Xin, Shaokun; Wang, Hongjie; Zuo, Ran; Wei, Xiaolu; Yang, Jian; Zhao, Haiyu; Bian, Baolin

2017-11-01

Protoberberine alkaloids including berberine, palmatine, jatrorrhizine, coptisine, and epiberberine are major components in many medicinal plants. They have been widely used for the treatment of cancer, inflammation, diabetes, depression, hypertension, and various infectious areas. However, the metabolism of five protoberberine alkaloids among different species has not been clarified previously. In order to elaborate on the in vitro metabolism of them, a comparative analysis of their metabolic profile in rat, rhesus monkey, and human liver microsomes was carried out using ultrahigh-performance liquid chromatography coupled with a high-resolution linear trap quadrupole-Orbitrap mass spectrometer (UHPLC-electrospray ionization-Orbitrap MS) for the first time. Each metabolite was identified and semiquantified by its accurate mass data and peak area. Fifteen metabolites were characterized based on accurate MS/MS spectra and the proposed MS/MS fragmentation pathways including demethylation, hydroxylation, and methyl reduction. Among them, the content of berberine metabolites in human liver microsomes was similar with those in rhesus monkey liver microsomes, whereas berberine in rat liver microsomes showed no demethylation metabolites and the content of metabolites showed significant differences with that in human liver microsomes. On the contrary, the metabolism of palmatine in rat liver microsomes resembled that in human liver microsomes. The content of jatrorrhizine metabolites presented obvious differences in all species. The HR-ESI-MS/MS fragmentation behavior of protoberberine alkaloids and their metabolic profile in rat, rhesus monkey, and human liver microsomes were investigated for the first time. The results demonstrated that the biotransformation characteristics of protoberberine alkaloids among different species had similarities as well differences that would be beneficial for us to better understand the pharmacological activities of protoberberine alkaloids

The serotonin transporter in rhesus monkey brain: comparison of DASB and citalopram binding sites

International Nuclear Information System (INIS)

Zeng Zhizhen; Chen, T.-B.; Miller, Patricia J.; Dean, Dennis; Tang, Y.S.; Sur, Cyrille; Williams, David L.

2006-01-01

We have characterized the interaction of the serotonin transporter ligand [ 3 H]-N,N-dimethyl-2-(2-amino-4-cyanophenylthio)-benzylamine (DASB) with rhesus monkey brain in vitro using tissue homogenate binding and autoradiographic mapping. [ 3 H]-DASB, a tritiated version of the widely used [ 11 C] positron emission tomography tracer, was found to selectively bind to a single population of sites with high affinity (K d =0.20±0.04 nM). The serotonin transporter density (B max ) obtained for rhesus frontal cortex was found to be 66±8 fmol/mg protein using [ 3 H]-DASB, similar to the B max value obtained using the reference radioligand [ 3 H]-citalopram, a well-characterized and highly selective serotonin reuptake inhibitor (83±22 fmol/mg protein). Specific binding sites of both [ 3 H]-DASB and [ 3 H]-citalopram were similarly and nonuniformly distributed throughout the rhesus central nervous system, in a pattern consistent with serotonin transporter localization reported for human brain. Regional serotonin transporter densities, estimated from optical densities of the autoradiographic images, were well correlated between the two radioligands. Finally, DASB and fluoxetine showed dose-dependent full inhibition of [ 3 H]-citalopram binding in a competition autoradiographic study, with K i values in close agreement with those obtained from rhesus brain homogenates. This side-by-side comparison of [ 3 H]-DASB and [ 3 H]-citalopram binding sites in rhesus tissue homogenates and in adjacent rhesus brain slices provides additional support for the use of [ 11 C]-DASB to assess the availability and distribution of serotonin transporters in nonhuman primates

The relationship between refractive and biometric changes during Edinger–Westphal stimulated accommodation in rhesus monkeys

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Vilupuru, Abhiram S.; Glasser, Adrian

2010-01-01

Experiments were undertaken to understand the relationship between dynamic accommodative refractive and biometric (lens thickness (LT), anterior chamber depth (ACD) and anterior segment length (ASL=ACD+LT)) changes during Edinger–Westphal stimulated accommodation in rhesus monkeys. Experiments were conducted on three rhesus monkeys (aged 11·5, 4·75 and 4·75 years) which had undergone prior, bilateral, complete iridectomies and implantation of a stimulating electrode in the Edinger–Westphal (EW) nucleus. Accommodative refractive responses were first measured dynamically with video-based infrared photorefraction and then ocular biometric responses were measured dynamically with continuous ultrasound biometry (CUB) during EW stimulation. The same stimulus amplitudes were used for the refractive and biometric measurements to allow them to be compared. Main sequence relationships (ratio of peak velocity to amplitude) were calculated. Dynamic accommodative refractive changes are linearly correlated with the biometric changes and accommodative biometric changes in ACD, ASL and LT show systematic linear correlations with increasing accommodative amplitudes. The relationships are relatively similar for the eyes of the different monkeys. Dynamic analysis showed that main sequence relationships for both biometry and refraction are linear. Although accommodative refractive changes in the eye occur primarily due to changes in lens surface curvature, the refractive changes are well correlated with A-scan measured accommodative biometric changes. Accommodative changes in ACD, LT and ASL are all well correlated over the full extent of the accommodative response. PMID:15721617

Measurement of rhesus monkey (Macaca mulatta) apolipoprotein B in serum by radioimmunoassay: comparison of immunoreactivities of rhesus and human low density lipoproteins

International Nuclear Information System (INIS)

Karlin, J.B.; Juhn, D.J.; Fless, G.; Scanu, A.M.; Rubenstein, A.H.

1978-01-01

A sensitive and specific double antibody radioimmunoassay for the major apolipoprotein (apoB) of rhesus (Macaca mulatta) serum very low density lipoprotein (VLDL) and low density lipoprotein (LDL) is described. The antiserum was raised to LDL (d 1.030 to 1.040 g/ml) and the LDL 2 (d 1.020 to 1.050 g/ml) was labeled with 125 I by the chloramine-T or iodine monochloride method. The assay, which was sensitive to 0.02 to 0.5 μg of LDL 2 , had an interassay coefficient of variation of 4.5%. This assay was successfully used to measure apoB in the whole serum and low density lipoproteins of control monkeys maintained on a standard Purina monkey chow (PMC) diet and of three groups of monkeys fed atherogenic diets: an average American diet, a 25% peanut oil and 2% cholesterol-supplemented PMC diet, and a 25% coconut oil and 2% cholesterol-supplemented PMC diet

Impaired performance from brief social isolation of rhesus monkeys (Macaca mulatta) - A multiple video-task assessment

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Washburn, David A.; Rumbaugh, Duane M.

1991-01-01

Social isolation has been demonstrated to produce profound and lasting psychological effects in young primates. In the present investigation, two adult rhesus monkeys (Macaca mulatta) were isolated from one another for up to 6 days and tested on 7 video tasks designed to assess psychomotor and cognitive functioning. Both the number and quality (i.e., speed and accuracy) of responses were significantly compromised in the social isolation condition relative to levels in which the animals were tested together. It is argued that adult rhesus are susceptible to performance disruption by even relatively brief social isolation, and that these effects can best be assessed by a battery of complex and sensitive measures.

Analogical reasoning and the differential outcome effect: transitory bridging of the conceptual gap for rhesus monkeys (Macaca mulatta).

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Flemming, Timothy M; Thompson, Roger K R; Beran, Michael J; Washburn, David A

2011-07-01

Monkeys, unlike chimpanzees and humans, have a marked difficulty acquiring relational matching-to-sample (RMTS) tasks that likely reflect the cognitive foundation upon which analogical reasoning rests. In the present study, rhesus monkeys (Macaca mulatta) completed a categorical (identity and nonidentity) RMTS task with differential reward (pellet ratio) and/or punishment (timeout ratio) outcomes for correct and incorrect choices. Monkeys in either differential reward-only or punishment-only conditions performed at chance levels. However, the RMTS performance of monkeys experiencing both differential reward and punishment conditions was significantly better than chance. Subsequently when all animals experienced nondifferential outcomes tests, their RMTS performance levels were at chance. These results indicate that combining differential reward and punishment contingencies provide an effective, albeit transitory, scaffolding for monkeys to judge analogical relations-between-relations. PsycINFO Database Record (c) 2011 APA, all rights reserved

Donepezil- and scopolamine-induced rCMRglu changes assessed by PET in conscious rhesus monkeys

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Asai, Makoto; Fujikawa, Akihiko; Noda, Akihiro; Miyoshi, Sosuke; Nishimura, Shintaro; Matsuoka, Nobuya

2009-01-01

[ 18 F]Fluoro-2-deoxyglucose positron emission tomography (FDG-PET) is a useful tool for measuring the regional cerebral metabolic rate of glucose (rCMRglu), which is an index of neuronal activity. Donepezil, an acetylcholine esterase inhibitor (AChEI), has been recommended as a treatment option for patients with Alzheimer's disease (AD). We aimed to characterize the effects of donepezil on rCMRglu using FDG-PET in non-human primates. We investigated the effects of administration of donepezil (500 μg/kg, intramuscularly (i.m.)), the non-selective muscarinic ACh receptor antagonist scopolamine (30 μg/kg, i.m.), and the coadministration of both drugs on the rCMRglu of conscious young rhesus monkeys. Donepezil increased the rCMRglu in all regions of interest except in the thalamus. Scopolamine treatment also increased the rCMRglu in all regions of interest except the cerebellum and thalamus. However, these effects disappeared with coadministration of the drugs. This PET study showed that administration of donepezil or scopolamine alone increased the rCMRglu in conscious rhesus monkeys. We also found that the donepezil-induced increase was abolished by simultaneous administration of scopolamine, suggesting that muscarinic ACh receptor function plays an important role in the effect of donepezil. (author)

Reproducibility of Perfusion Parameters of Optic Disc and Macula in Rhesus Monkeys by Optical Coherence Tomography Angiography.

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Li, Jing; Yang, Yi-Quan; Yang, Di-Ya; Liu, Xiang-Xiang; Sun, Yun-Xiao; Wei, Shi-Fei; Wang, Ning-Li

2016-05-05

Optical coherence tomography (OCT) angiography is a novel technique by which we can detect the local perfusion of fundus directly. The aim of this study was to evaluate the reproducibility of optic disc and macular flow perfusion parameters in rhesus monkeys using OCT angiography. Eighteen healthy monkeys (18 eyes) were subjected to optic disc and macula flow index measurements via a high-speed and high-resolution spectral-domain OCT XR Avanti with a split-spectrum amplitude de-correlation angiography algorithm. Right eye was imaged 3 times during the first examination and once during each of the two following examinations. The intra-visit and inter-visit intraclass correlation coefficients (ICCs) were both determined. The average flow indices of the four optic disc area layers were 0.171 ± 0.009 (optic nerve head), 0.015 ± 0.004 (vitreous), 0.052 ± 0.009 (radial peripapillary capillary), and 0.167 ± 0.011 (choroid). Average flow indices of the four macula area layers were 0.044 ± 0.011 (superficial retina), 0.036 ± 0.011 (deep retina), 0.016 ± 0.009 (outer retina), and 0.155 ± 0.013 (choroid). Intra-visit (ICC value: 0.821-0.954) and inter-visit (ICC value: 0.844-0.899) repeatability were both high. The study is about the reproducibility of optic disc and macular perfusion parameters as measured by OCT angiography in healthy rhesus monkeys. Flow index measurement reproducibility is high for both the optic disc and macula of normal monkey eyes. OCT angiography might be a useful technique to assess changes when examining monkeys with experimental ocular diseases.

Lack of dose dependent kinetics of methyl salicylate-2-O-β-D-lactoside in rhesus monkeys after oral administration.

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He, Yangyang; Yan, Yu; Zhang, Tiantai; Ma, Yinzhong; Zhang, Wen; Wu, Ping; Song, Junke; Wang, Shuang; Du, Guanhua

2015-04-22

Methyl salicylate-2-O-β-d-lactoside (MSL) is one of the main active components isolated from Gaultheria yunnanensis, which is a traditional Chinese medicine used to treat arthritis and various aches and pains. Pharmacological researches showed that MSL had various effective activities in both in vivo and in vitro experiments. However, the pharmacokinetics features and oral bioavailability of MSL in primates were not studied up to now. To study the pharmacokinetics of different doses of MSL in rhesus monkeys and investigate the absolute bioavailability of MSL after oral administration. Male and female rhesus monkeys were either orally administrated with MSL 200, 400 and 800 mg/kg or received an intravenous dose of 20mg/kg randomly. The levels of MSL and salicylic acid (SA) in plasma were simultaneous measured by a simple, sensitive and reproducible high performance liquid chromatography method. Mean peak plasma concentration values for groups treated with 200, 400 and 800 mg/kg doses ranged from 48.79 to 171.83 μg/mL after single-dose oral administration of MSL, and mean area under the concentration-time curve values ranged from 195.16 to 1107.76 μg/mL h. Poor linearity of the kinetics of SA after oral administration of MSL was observed in the regression analysis of the Cmax-dose plot (r(2)=0.812), CL-dose plot (r(2)=0.225) and AUC(0-t)-dose plot (r(2)=0.938). Absolute bioavailability of MSL was assessed to be 118.89 ± 57.50, 213.54 ± 58.98 and 168.72 ± 76.58%, respectively. Bioavailability of MSL after oral administration in rhesus monkeys was measured for the first time. Pharmacokinetics parameters did not appear to be dose proportional among the three oral doses of treatments, and MSL showed an apparent absolute bioavailability in excess of 100% in rhesus monkeys based on the present study. In addition, a rapid, sensitive and reliable HPLC method was established and demonstrated for the research of traditional Chinese medicine in this study. Copyright �

The serotonin transporter in rhesus monkey brain: comparison of DASB and citalopram binding sites

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Zeng Zhizhen [Imaging Department, Merck Research Laboratories, West Point, PA 19486 (United States)]. E-mail: zhizhen_zeng@merck.com; Chen, T.-B. [Imaging Department, Merck Research Laboratories, West Point, PA 19486 (United States); Miller, Patricia J. [Imaging Department, Merck Research Laboratories, West Point, PA 19486 (United States); Dean, Dennis [Labeled Compound Synthesis Group, Drug Metabolism, Merck Research Laboratories, Rahway, NJ 07065-0900 (United States); Tang, Y.S. [Labeled Compound Synthesis Group, Drug Metabolism, Merck Research Laboratories, Rahway, NJ 07065-0900 (United States); Sur, Cyrille [Imaging Department, Merck Research Laboratories, West Point, PA 19486 (United States); Williams, David L. [Imaging Department, Merck Research Laboratories, West Point, PA 19486 (United States)

2006-05-15

We have characterized the interaction of the serotonin transporter ligand [{sup 3}H]-N,N-dimethyl-2-(2-amino-4-cyanophenylthio)-benzylamine (DASB) with rhesus monkey brain in vitro using tissue homogenate binding and autoradiographic mapping. [{sup 3}H]-DASB, a tritiated version of the widely used [{sup 11}C] positron emission tomography tracer, was found to selectively bind to a single population of sites with high affinity (K {sub d}=0.20{+-}0.04 nM). The serotonin transporter density (B {sub max}) obtained for rhesus frontal cortex was found to be 66{+-}8 fmol/mg protein using [{sup 3}H]-DASB, similar to the B {sub max} value obtained using the reference radioligand [{sup 3}H]-citalopram, a well-characterized and highly selective serotonin reuptake inhibitor (83{+-}22 fmol/mg protein). Specific binding sites of both [{sup 3}H]-DASB and [{sup 3}H]-citalopram were similarly and nonuniformly distributed throughout the rhesus central nervous system, in a pattern consistent with serotonin transporter localization reported for human brain. Regional serotonin transporter densities, estimated from optical densities of the autoradiographic images, were well correlated between the two radioligands. Finally, DASB and fluoxetine showed dose-dependent full inhibition of [{sup 3}H]-citalopram binding in a competition autoradiographic study, with K {sub i} values in close agreement with those obtained from rhesus brain homogenates. This side-by-side comparison of [{sup 3}H]-DASB and [{sup 3}H]-citalopram binding sites in rhesus tissue homogenates and in adjacent rhesus brain slices provides additional support for the use of [{sup 11}C]-DASB to assess the availability and distribution of serotonin transporters in nonhuman primates.

Attempts at immunization against Malayan filariasis using X-irradiated infective larvae

International Nuclear Information System (INIS)

Ramachandran, C.P.

1975-01-01

Recent studies on immunity to helminthic infections have shown that some degree of protective immunity may be stimulated by inoculations of attenuated living worms or their metabolites. Although much on these lines has been done with several helminths, little if any has been done with filarial infections in general. Experiments were designed to observe the effects of attempted immunization in the rhesus monkey as well as the domestic cat by the use of attenuated infective larvae of Brugia malayi. The sub-periodic strain of Brugia malayi, the major filarial parasite of man in Malaysia, maintained in the laboratory on experimentally infected cats and rhesus monkeys were used for the preparation of X-irradiated vaccines as well as for challenge inoculations. Third-stage infective larvae of Brugia malayi were obtained from experimentally fed Aedes togoi mosquitoes. Infective larvae were irradiated by X-rays, using a Dermopan X-ray unit at exposures between 10 - 40 kR. Rhesus monkeys and cats were inoculated twice with 100 - 400 attenuated larvae per inoculation at 2 week intervals and challenged about a month later by inoculation of 100 normal larvae. Control animals for each vaccination dose as well as for challenge doses were maintained. In rhesus monkeys persistent immunity to challenge infections (expressed as failure to cause microfilaraemia) were obtained in animals vaccinated with 200 infective larvae attenuated by X-irradiation at 20000 R. Encouraged with the results obtained on rhesus monkeys, similar experiments on an enlarged scale using varying strengths of the vaccines were carried out on the domestic cat, which is a more receptive animal host for Brugia malayi. However, all cats vaccinated when challenged came down with patent infection indicating lack of any definite immunity. In all these experiments, results of vaccine control animals showed that inoculation of irradiated larvae was not followed by the infection of microfilaria in the blood, indicating

Perturbations de l'homéostasie lymphocytaire T chez le macaque rhésus chinois en phase aiguë d'infection par le SIVmac251

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Ponte, Rosalie

2014-01-01

As a model to study type 1 human immunodeficiency virus (HIV-1) pathogenesis, rhesus macaques infected with the simian immunodeficiency virus (SIV) are under extensive investigation. Two subspecies of rhesus macaques have been defined, based on a different geographic origin. Indian rhesus macaques exhibit a rapid disease progression and acute infection is characterized by a massive CD4 T-cell loss in the intestinal mucosa. This was associated to the translocation of bacterial products through...

Autophagy in retinal ganglion cells in a rhesus monkey chronic hypertensive glaucoma model.

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Shuifeng Deng

Full Text Available Primary open angle glaucoma (POAG is a neurodegenerative disease characterized by physiological intraocular hypertension that causes damage to the retinal ganglion cells (RGCs. In the past, RGC damage in POAG was suggested to have been attributed to RGC apoptosis. However, in the present study, we applied a model closer to human POAG through the use of a chronic hypertensive glaucoma model in rhesus monkeys to investigate whether another mode of progressive cell death, autophagy, was activated in the glaucomatous retinas. First, in the glaucomatous retinas, the levels of LC3B-II, LC3B-II/LC3B-I and Beclin 1 increased as demonstrated by Western blot analyses, whereas early or initial autophagic vacuoles (AVi and late or degraded autophagic vacuoles (AVd accumulated in the ganglion cell layer (GCL and in the inner plexiform layer (IPL as determined by transmission electron microscopy (TEM analysis. Second, lysosome activity and autophagosome-lysosomal fusion increased in the RGCs of the glaucomatous retinas, as demonstrated by Western blotting against lysosome associated membrane protein-1 (LAMP1 and double labeling against LC3B and LAMP1. Third, apoptosis was activated in the glaucomatous eyes with increased levels of caspase-3 and cleaved caspase-3 and an increased number of TUNEL-positive RGCs. Our results suggested that autophagy was activated in RGCs in the chronic hypertensive glaucoma model of rhesus monkeys and that autophagy may have potential as a new target for intervention in glaucoma treatment.

Anti-α4 antibody treatment blocks virus traffic to the brain and gut early, and stabilizes CNS injury late in infection.

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Jennifer H Campbell

2014-12-01

Full Text Available Four SIV-infected monkeys with high plasma virus and CNS injury were treated with an anti-α4 blocking antibody (natalizumab once a week for three weeks beginning on 28 days post-infection (late. Infection in the brain and gut were quantified, and neuronal injury in the CNS was assessed by MR spectroscopy, and compared to controls with AIDS and SIV encephalitis. Treatment resulted in stabilization of ongoing neuronal injury (NAA/Cr by 1H MRS, and decreased numbers of monocytes/macrophages and productive infection (SIV p28+, RNA+ in brain and gut. Antibody treatment of six SIV infected monkeys at the time of infection (early for 3 weeks blocked monocyte/macrophage traffic and infection in the CNS, and significantly decreased leukocyte traffic and infection in the gut. SIV - RNA and p28 was absent in the CNS and the gut. SIV DNA was undetectable in brains of five of six early treated macaques, but proviral DNA in guts of treated and control animals was equivalent. Early treated animals had low-to-no plasma LPS and sCD163. These results support the notion that monocyte/macrophage traffic late in infection drives neuronal injury and maintains CNS viral reservoirs and lesions. Leukocyte traffic early in infection seeds the CNS with virus and contributes to productive infection in the gut. Leukocyte traffic early contributes to gut pathology, bacterial translocation, and activation of innate immunity.

Anti-α4 antibody treatment blocks virus traffic to the brain and gut early, and stabilizes CNS injury late in infection.

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Campbell, Jennifer H; Ratai, Eva-Maria; Autissier, Patrick; Nolan, David J; Tse, Samantha; Miller, Andrew D; González, R Gilberto; Salemi, Marco; Burdo, Tricia H; Williams, Kenneth C

2014-12-01

Four SIV-infected monkeys with high plasma virus and CNS injury were treated with an anti-α4 blocking antibody (natalizumab) once a week for three weeks beginning on 28 days post-infection (late). Infection in the brain and gut were quantified, and neuronal injury in the CNS was assessed by MR spectroscopy, and compared to controls with AIDS and SIV encephalitis. Treatment resulted in stabilization of ongoing neuronal injury (NAA/Cr by 1H MRS), and decreased numbers of monocytes/macrophages and productive infection (SIV p28+, RNA+) in brain and gut. Antibody treatment of six SIV infected monkeys at the time of infection (early) for 3 weeks blocked monocyte/macrophage traffic and infection in the CNS, and significantly decreased leukocyte traffic and infection in the gut. SIV - RNA and p28 was absent in the CNS and the gut. SIV DNA was undetectable in brains of five of six early treated macaques, but proviral DNA in guts of treated and control animals was equivalent. Early treated animals had low-to-no plasma LPS and sCD163. These results support the notion that monocyte/macrophage traffic late in infection drives neuronal injury and maintains CNS viral reservoirs and lesions. Leukocyte traffic early in infection seeds the CNS with virus and contributes to productive infection in the gut. Leukocyte traffic early contributes to gut pathology, bacterial translocation, and activation of innate immunity.

Functional analysis of frequently expressed Chinese rhesus macaque MHC class I molecules Mamu-A1*02601 and Mamu-B*08301 reveals HLA-A2 and HLA-A3 supertypic specificities

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Southwood, Scott; Solomon, Christopher; Hoof, Ilka

2011-01-01

The Simian immunodeficiency virus (SIV)-infected Indian rhesus macaque (Macaca mulatta) is the most established model of HIV infection and AIDS-related research, despite the potential that macaques of Chinese origin is a more relevant model. Ongoing efforts to further characterize the Chinese...... populations. In this study, we have characterized two additional alleles expressed with high frequency in Chinese rhesus macaques, Mamu-A1*02601 and Mamu-B*08301. Upon the development of MHC–peptide-binding assays and definition of their associated motifs, we reveal that these Mamu alleles share peptide...

Biologically-directed modeling reflects cytolytic clearance of SIV-infected cells in vivo in macaques.

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W David Wick

Full Text Available The disappointing outcomes of cellular immune-based vaccines against HIV-1 despite strong evidence for the protective role of CD8⁺ T lymphocytes (CTLs has prompted revisiting the mechanisms of cellular immunity. Prior data from experiments examining the kinetics of Simian Immunodeficiency Virus (SIV clearance in infected macaques with or without in vivo CD8 depletion were interpreted as refuting the concept that CTLs suppress SIV/HIV by direct killing of infected cells. Here we briefly review the biological evidence for CTL cytolytic activity in viral infections, and utilize biologically-directed modeling to assess the possibility of a killing mechanism for the antiviral effect of CTLs, taking into account the generation, proliferation, and survival of activated CD4⁺ and CD8⁺ T lymphocytes, as well as the life cycle of the virus. Our analyses of the published macaque data using these models support a killing mechanism, when one considers T lymphocyte and HIV-1 lifecycles, and factors such as the eclipse period before release of virions by infected cells, an exponential pattern of virion production by infected cells, and a variable lifespan for acutely infected cells. We conclude that for SIV/HIV pathogenesis, CTLs deserve their reputation as being cytolytic.

Hypercytotoxicity and rapid loss of NKp44+ innate lymphoid cells during acute SIV infection.

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Haiying Li

2014-12-01

Full Text Available HIV/SIV infections break down the integrity of the gastrointestinal mucosa and lead to chronic immune activation and associated disease progression. Innate lymphoid cells (ILCs, distinguishable by high expression of NKp44 and RORγt, play key roles in mucosal defense and homeostasis, but are depleted from gastrointestinal (GI tract large bowel during chronic SIV infection. However, less is known about the kinetics of ILC loss, or if it occurs systemically. In acute SIV infection, we found a massive, up to 8-fold, loss of NKp44+ILCs in all mucosae as early as day 6 post-infection, which was sustained through chronic disease. Interestingly, no loss of ILCs was observed in mucosa-draining lymph nodes. In contrast, classical NK cells were not depleted either from gut or draining lymph nodes. Both ILCs and NK cells exhibited significantly increased levels of apoptosis as measured by increased Annexin-V expression, but while classical NK cells also showed increased proliferation, ILCs did not. Interestingly, ILCs, which are normally noncytolytic, dramatically upregulated cytotoxic functions in acute and chronic infection and acquired a polyfunctional phenotype secreting IFN-γ, MIP1-β, and TNF-α, but decreased production of the prototypical cytokine, IL-17. Classical NK cells had less dramatic functional change, but upregulated perforin expression and increased cytotoxic potential. Finally, we show that numerical and functional loss of ILCs was due to increased apoptosis and ROR γt suppression induced by inflammatory cytokines in the gut milieu. Herein we demonstrate the first evidence for acute, systemic, and permanent loss of mucosal ILCs during SIV infection associated with reduction of IL-17. The massive reduction of ILCs involves apoptosis without compensatory de novo development/proliferation, but the full mechanism of depletion and the impact of functional change so early in infection remain unclear.

Selective bilateral amygdala lesions in rhesus monkeys fail to disrupt object reversal learning.

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Izquierdo, Alicia; Murray, Elisabeth A

2007-01-31

Neuropsychological studies in nonhuman primates have led to the view that the amygdala plays an essential role in stimulus-reward association. The main evidence in support of this idea is that bilateral aspirative or radiofrequency lesions of the amygdala yield severe impairments on object reversal learning, a task that assesses the ability to shift choices of objects based on the presence or absence of food reward (i.e., reward contingency). The behavioral effects of different lesion techniques, however, can vary. The present study therefore evaluated the effects of selective, excitotoxic lesions of the amygdala in rhesus monkeys on object reversal learning. For comparison, we tested the same monkeys on a task known to be sensitive to amygdala damage, the reinforcer devaluation task. Contrary to previous results based on less selective lesion techniques, monkeys with complete excitotoxic amygdala lesions performed object reversal learning as quickly as controls. As predicted, however, the same operated monkeys were impaired in making object choices after devaluation of the associated food reinforcer. The results suggest two conclusions. First, the results demonstrate that the amygdala makes a selective contribution to stimulus-reward association; the amygdala is critical for guiding object choices after changes in reward value but not after changes in reward contingency. Second, the results implicate a critical contribution to object reversal learning of structures nearby the amygdala, perhaps the subjacent rhinal cortex.

The impact of early immune destruction on the kinetics of postacute viral replication in rhesus monkey infected with the simian-human immunodeficiency virus 89.6P

International Nuclear Information System (INIS)

Zhang Zhiqiang; Schleif, William A.; Casimiro, Danilo R.; Handt, Larry; Chen, Minchun; Davies, Mary-Ellen; Liang Xiaoping; Fu Tongming; Tang Aimin; Wilson, Keith A.; McElhaugh, Michael; Carella, Anthony; Tan, Charles; Connolly, Brett; Hill, Susan; Klein, Hilton; Emini, Emilio A.; Shiver, John W.

2004-01-01

Set-point viral load is positively correlated with the extent of initial viral replication in pathogenic simian-human immunodeficiency virus (SHIV) infection. To elucidate the mechanisms underlying the correlation, we conducted a systematic investigation in rhesus monkeys infected with the highly pathogenic SHIV 89.6P. This model is widely used in the preclinical evaluation of AIDS vaccine candidates and a thorough understanding of the model's biology is important to the proper interpretation of these evaluations. We found that the levels of peak viremia were positively correlated not only with the levels of set-point viremia but, importantly, with the extent of initial overall immune destruction as indicated by the degree of CD4 + T cell depletion and lymph node germinal center (GC) formation. The extent of initial overall immune destruction was inversely correlated with subsequent development and maintenance of virus-specific cellular and humoral immune responses. Thus, these data suggest that the extent of early immune damage determines the development and durability of virus-specific immunity, thereby playing a critical role in establishing the levels of set-point viral replication in SHIV infection. Vaccines that limit both the initial viral replication and the extent of early immune damage will therefore mediate long-term virus replication control and mitigation of long-term immune destruction in this model of immunodeficiency virus infection

In vitro incorporation of (U-C/sup 14/)-glucose and (1-C/sup 14/)-sodium acetate in peripheral nerves of malnourished young rhesus monkeys

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Rana, S V; Mehta, S; Chopra, J S; Nain, C K; Mehta, J; Dhand, U K

1984-01-01

The effect of protein calorie malnutrition (PCM) on synthesis of lipids in peripheral nerves was studied by in vitro incorporation of (U-C/sup 14/)-glucose and (1-C/sup 14/)-sodium acetate. Ulnar and tibial nerves obtained from five young rhesus monkeys with PCM, five rehabilitated monkeys, and five control monkeys were incubated for 2 h with the radioactive precursors. Uptake of both radioactive precursors in whole peripheral nerves as well as myelin marker lipids was significantly decreased in animals with PCM. However, uptake returned to normal in rehabilitated monkeys.

Radioimmunoassay of parathyroid hormone (parathyrin) in monkey and man

International Nuclear Information System (INIS)

Hargis, G.K.; Williams, G.A.; Reynolds, W.A.; Kawahara, W.; Jackson, B.; Bowser, E.N.; Pitkin, R.M.

1977-01-01

A radioimmunoassay for rhesus monkey and human innumoreactive parathyrin was developed in which a selected anti-bovine parathyrin antiserum, radioiodinated purified bovine parathyrin tracer, and human parathyroid tissue-culture media standards were used. The resulting data indicate that the method is sensitive, specific, accurate and reproducible; it is valid for both the rhesus monkey and the human; the serum immunoreactive parathyrin concentration of the monkey is essentially the same as that in man; monkey immunoreactive parathyrin responds to changes in serum calcium concentration similarly to that in man; and the rhesus monkey is therefore a suitable species in which to study parathyroid physiology, from which conclusions can be applied to the human

Radioprotective effects of CBLB502 on γ-radiated Rhesus monkey

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Xing SHEN

2015-06-01

Full Text Available Objective　A Rhesus monkey model was employed to study the radioprotective effects of a Toll-like receptor 5 agonist, CBLB502, against 7.0Gy whole-body irradiation of 60Co gamma-rays. Methods　Thirty animals were assigned to a placebo treatment group, a WR-2721 positive control group, and three CBLB502 treatment groups (n=6 animals/group. Each animal was irradiated with 7.0Gy 60Co γ and given CBLB502 at 2.5, 10 and 40μg/kg, respectively in treatment groups, or WR-2721 at 30mg/kg, or physiological saline 0.3ml/kg for the placebo treatment group. The treatment was given once by intramuscular injection 30 min before irradiation. All irradiated animals received symptomatic treatment based on same guidelines. General observation, peripheral blood tests, hemopoietic progenitor cell colony-counting, and histopathological examination were performed. Results　We found that 10 or 40μg/kg CBLB502 treatment resulted in 100% survival, while the survival rate was 33% in placebo treatment group. Hematopoietic recovery in the WR-2721 treatment group was marginally superior to the irradiation control group. Nadirs of peripheral white cell and platelet counts of animals treated with 40μg/kg of CBLB502 were significantly higher than those of the placebo treatment group (P<0.05. CBLB502 at 40μg/kg also gave a shortened duration of low platelet count, earlier recovery time, reduced the amount of blood transfusion and damage to the bone marrow and intestine. Conclusion　All Rhesus monkeys irradiated with 7.0Gy 60Co γ-rays would suffer from severe acute radiation sickness of hematopoietic system. CBLB502 at 40μg/kg is radioprotective in this model and a single intramuscular injection of CBLB502 in a dose of 40μg/kg 30min before irradiation gives better radioprotective effects than WR-2721. DOI: 10.11855/j.issn.0577-7402.2015.04.07

Evidence for alterations in luteinizing hormone secreted in rhesus monkeys with normal and inadequate luteal phases using radioreceptor and radioimmunoassay

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Sakai, C.N.; Channing, C.P.

1979-05-01

A radioreceptor assay (RRA) using porcine granulosa cells and (/sup 125/I)hCG was developed and validated for the measurement of LH or CG. The RRA was used in conjunction with a heterologous RIA employing antiserum against ovine LH and (/sup 125/I)ovine LH (RIA) to measure serum LH in the rhesus monkey throughout the menstrual cycle. Discrepancies were found in the measurement of serum LH using RRA and RIA. Measurements of serum LH using RIA were consistently higher than the measurements of serum LH using RRA in serum from adult intact female and male monkeys and hypophysectomized, ovariectomized, and pregnant monkeys.

On the nature of directed behavior to drug-associated light cues in rhesus monkeys (Macaca mulatta).

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Reilly, Mark P; Berndt, Sonja I; Woods, James H

2016-11-01

The present study investigated the role of drug-paired stimuli in controlling the behavior of rhesus monkeys. Systematic observations were made with nine monkeys who had a history of drug self-administration; they had been lever pressing to produce intravenous infusions of various drugs. These observations revealed that the stimulus light co-occurring with drug infusion produced robust and cue-directed behavior such as orienting, touching and biting. Experiment 1 showed that this light-directed behavior would occur in naïve monkeys exposed to a Pavlovian pairing procedure. Four monkeys were given response-independent injections of cocaine. In two monkeys, a red light preceded cocaine injections by 5 s, and a green light co-occurred with the 5-s cocaine injections. In the other two monkeys, the light presentations and cocaine injections occurred independently. Light-directed behavior occurred in all four monkeys within the first couple of trials and at high levels but decreased across sessions. The cocaine-paired stimulus maintained behavior longer and at higher levels than the uncorrelated stimuli. Furthermore, light-directed behavior was not maintained when cocaine was replaced with saline. Light-directed behavior did not occur in the absence of the lights. When these monkeys were subsequently trained to lever press for cocaine, light-directed behavior increased to levels higher than previously observed. Behavior directed towards drug-paired stimuli is robust, reliable and multiply determined; the mechanisms underlying this activity likely include Pavlovian conditioning, stimulus novelty, habituation and operant conditioning.

Discovery and full genome characterization of two highly divergent simian immunodeficiency viruses infecting black-and-white colobus monkeys (Colobus guereza) in Kibale National Park, Uganda.

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Lauck, Michael; Switzer, William M; Sibley, Samuel D; Hyeroba, David; Tumukunde, Alex; Weny, Geoffrey; Taylor, Bill; Shankar, Anupama; Ting, Nelson; Chapman, Colin A; Friedrich, Thomas C; Goldberg, Tony L; O'Connor, David H

2013-10-21

African non-human primates (NHPs) are natural hosts for simian immunodeficiency viruses (SIV), the zoonotic transmission of which led to the emergence of HIV-1 and HIV-2. However, our understanding of SIV diversity and evolution is limited by incomplete taxonomic and geographic sampling of NHPs, particularly in East Africa. In this study, we screened blood specimens from nine black-and-white colobus monkeys (Colobus guereza occidentalis) from Kibale National Park, Uganda, for novel SIVs using a combination of serology and "unbiased" deep-sequencing, a method that does not rely on genetic similarity to previously characterized viruses. We identified two novel and divergent SIVs, tentatively named SIVkcol-1 and SIVkcol-2, and assembled genomes covering the entire coding region for each virus. SIVkcol-1 and SIVkcol-2 were detected in three and four animals, respectively, but with no animals co-infected. Phylogenetic analyses showed that SIVkcol-1 and SIVkcol-2 form a lineage with SIVcol, previously discovered in black-and-white colobus from Cameroon. Although SIVkcol-1 and SIVkcol-2 were isolated from the same host population in Uganda, SIVkcol-1 is more closely related to SIVcol than to SIVkcol-2. Analysis of functional motifs in the extracellular envelope glycoprotein (gp120) revealed that SIVkcol-2 is unique among primate lentiviruses in containing only 16 conserved cysteine residues instead of the usual 18 or more. Our results demonstrate that the genetic diversity of SIVs infecting black-and-white colobus across equatorial Africa is greater than previously appreciated and that divergent SIVs can co-circulate in the same colobine population. We also show that the use of "unbiased" deep sequencing for the detection of SIV has great advantages over traditional serological approaches, especially for studies of unknown or poorly characterized viruses. Finally, the detection of the first SIV containing only 16 conserved cysteines in the extracellular envelope protein

Development of a translational model to screen medications for cocaine use disorder I: Choice between cocaine and food in rhesus monkeys.

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Johnson, Amy R; Banks, Matthew L; Blough, Bruce E; Lile, Joshua A; Nicholson, Katherine L; Negus, S Stevens

2016-08-01

Homologous cocaine self-administration procedures in laboratory animals and humans may facilitate translational research for medications development to treat cocaine dependence. This study, therefore, sought to establish choice between cocaine and an alternative reinforcer in rhesus monkeys responding under a procedure back-translated from previous human studies and homologous to a human laboratory procedure described in a companion paper. Four rhesus monkeys with chronic indwelling intravenous catheters had access to cocaine injections (0, 0.043, 0.14, or 0.43mg/kg/injection) and food (0, 1, 3, or 10 1g banana-flavored food pellets). During daily 5h sessions, a single cocaine dose and a single food-reinforcer magnitude were available in 10 30-min trials. During the initial "sample" trial, the available cocaine and food reinforcer were delivered non-contingently. During each of the subsequent nine "choice" trials, responding could produce either the cocaine or food reinforcer under an independent concurrent progressive-ratio schedule. Preference was governed by the cocaine dose and food-reinforcer magnitude, and increasing cocaine doses produced dose-dependent increases in cocaine choice at all food-reinforcer magnitudes. Effects of the candidate medication lisdexamfetamine (0.32-3.2mg/kg/day) were then examined on choice between 0.14mg/kg/injection cocaine and 10 pellets. Under baseline conditions, this reinforcer pair maintained an average of approximately 6 cocaine and 3 food choices. Lisdexamfetamine dose-dependently decreased cocaine choice in all monkeys, but food choice was not significantly altered. These results support utility of this procedure in rhesus monkeys as one component of a platform for translational research on medications development to treat cocaine use disorder. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Therapeutic effect of rhIL-11 administered at different times on acute radiation sickness in rhesus monkeys

International Nuclear Information System (INIS)

Hao Jing; Luo Qingliang; Xiong Guolin; Liu Xiaolan; Qiu Liling; Chen Guozhi; Huang Ying; Ge Ping; Geng Yu; Sun Liansheng; Dong Bo; Li Yuanmin; Chen Wangqiu; Shen Chun

2001-01-01

Objective: The author describes the therapeutic effect of recombinant human interleukin-11 (rhIL-11) administered at different times on acute radiation sickness in monkeys. Methods: Rhesus monkeys irradiated with 3.0 Gy 60 Co γ rays were divided into 3 groups. One group was the control administered with vehicle, the second one was subjected to administer rhIL-11 on days 0-13 after TBI (60 μg·kg -1 ·d -1 , sc) and the third one to administer rhIL-11 on days 13-26 after TBI at the same doses. Results: The early treated group had higher platelet nadirs compared with that of the other two. The duration of platelet and leukocyte numbers below 50% of their baseline values shortened significantly in animals treated with rhIL-11, especially in the early treated group. During the first week after irradiation, the early treated group had lower erythrocyte count compared with the control, but it began to rise at day 19 after irradiation. Semi-solid bone marrow cell culture demonstrated that rhIL-11 could stimulate bone marrow cells to form more CFU-MK, CFU-Mix, CFU-E, BFU-E and CFU-GM in vitro. The authors also got the same results in histopathological observation. Conclusion: rhIL-11 administered at different times can not only accelerate the haematopoietic recovery of acute radiation sickness in rhesus monkeys, but also result in better therapeutic effect when administered earlier

Clustering of PCOS-like traits in naturally hyperandrogenic female rhesus monkeys.

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Abbott, D H; Rayome, B H; Dumesic, D A; Lewis, K C; Edwards, A K; Wallen, K; Wilson, M E; Appt, S E; Levine, J E

2017-04-01

Do naturally occurring, hyperandrogenic (≥1 SD of population mean testosterone, T) female rhesus monkeys exhibit traits typical of women with polycystic ovary syndrome (PCOS)? Hyperandrogenic female monkeys exhibited significantly increased serum levels of androstenedione (A4), 17-hydroxyprogesterone (17-OHP), estradiol (E2), LH, antimullerian hormone (AMH), cortisol, 11-deoxycortisol and corticosterone, as well as increased uterine endometrial thickness and evidence of reduced fertility, all traits associated with PCOS. Progress in treating women with PCOS is limited by incomplete knowledge of its pathogenesis and the absence of naturally occurring PCOS in animal models. A female macaque monkey, however, with naturally occurring hyperandrogenism, anovulation and polyfollicular ovaries, accompanied by insulin resistance, increased adiposity and endometrial hyperplasia, suggests naturally occurring origins for PCOS in nonhuman primates. As part of a larger study, circulating serum concentrations of selected pituitary, ovarian and adrenal hormones, together with fasted insulin and glucose levels, were determined in a single, morning blood sample obtained from 120 apparently healthy, ovary-intact, adult female rhesus monkeys (Macaca mulatta) while not pregnant or nursing. The monkeys were then sedated for somatometric and ultrasonographic measurements. Female monkeys were of prime reproductive age (7.2 ± 0.1 years, mean ± SEM) and represented a typical spectrum of adult body weight (7.4 ± 0.2 kg; maximum 12.5, minimum 4.6 kg). Females were defined as having normal (n = 99) or high T levels (n = 21; ≥1 SD above the overall mean, 0.31 ng/ml). Electronic health records provided menstrual and fecundity histories. Steroid hormones were determined by tandem LC-MS-MS; AMH was measured by enzymeimmunoassay; LH, FSH and insulin were determined by radioimmunoassay; and glucose was read by glucose meter. Most analyses were limited to 80 females (60 normal T, 20 high T) in

Study of the safety, immunogenicity and efficacy of attenuated and killed Leishmania (Leishmania major vaccines in a rhesus monkey (Macaca mulatta model of the human disease

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VF Amaral

2002-10-01

Full Text Available We have compared the efficacy of two Leishmania (Leishmania major vaccines, one genetically attenuated (DHFR-TS deficient organisms, the other inactivated [autoclaved promastigotes (ALM with bacillus Calmete-Guérin (BCG], in protecting rhesus macaques (Macaca mulatta against infection with virulent L. (L. major. Positive antigen-specific recall proliferative response was observed in vaccinees (79% in attenuated parasite-vaccinated monkeys, versus 75% in ALM-plus-BCG-vaccinated animals, although none of these animals exhibited either augmented in vitro gamma interferon (IFN-g production or positive delayed-type hypersensitivity (DTH response to the leishmanin skin test prior to the challenge. Following challenge, there were significant differences in blastogenic responses (p < 0.05 between attenuated-vaccinated monkeys and naïve controls. In both vaccinated groups very low levels of antibody were found before challenge, which increased after infective challenge. Protective immunity did not follow vaccination, in that monkeys exhibited skin lesion at the site of challenge in all the groups. The most striking result was the lack of pathogenicity of the attenuated parasite, which persisted in infected animals for up to three months, but were incapable of causing disease under the conditions employed. We concluded that both vaccine protocols used in this study are safe in primates, but require further improvement for vaccine application.

Seroprevalence of simian immunodeficiency virus in wild and captive born Sykes' monkeys (Cercopithecus mitis) in Kenya

OpenAIRE

Otsyula Moses G; Robinson James; Elliott Debra; Munene Elephas; Ellis Brett R; Michael Scott F

2004-01-01

Abstract Background The Sykes' monkey and related forms (Cercopithecus mitis) make up an abundant, widespread and morphologically diverse species complex in eastern Africa that naturally harbors a distinct simian immunodeficiency virus (SIVsyk). We carried out a retrospective serological survey of SIV infection from both wild and captive Sykes' monkeys from Kenya. We compared two commercially available, cross-reactive ELISA tests using HIV antigens with a novel SIVsyk antigen-specific Western...

Executive function is less sensitive to estradiol than spatial memory: performance on an analog of the card sorting test in ovariectomized aged rhesus monkeys.

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Lacreuse, A; Chhabra, R K; Hall, M J; Herndon, J G

2004-09-30

Functions supported by the frontal lobes are particularly sensitive to the detrimental effects of aging. Recent studies on postmenopausal women find that estrogen replacement therapy benefits performance on tasks dependent on the frontal lobes. To determine whether estrogen has a similar influence in a rhesus monkey model of menopause, we tested five aged, long-term ovariectomized rhesus monkeys in a modified version of the Wisconsin Card Sort test which had been adapted to the nonhuman primate. In this test, monkeys had to select 3-D objects based either on color (blue, red, yellow) or shape (block, tube, cup) and had to be able to switch their response as a function of reinforcement contingencies. The monkeys were treated with placebo and ethinyl estradiol (EE2, 450 ng/kg/day) in alternation with each successive test. Contrary to our hypothesis, estradiol treatment did not affect performance. Because previous studies in the same monkeys [Neurobiol. Aging 23 (2002) 589] had shown that EE2 improves performance on a spatial memory task dependent on the hippocampus, but not on another task dependent upon the frontal lobes (the delayed response), we conclude that executive processes may be less sensitive to the effects of estradiol than hippocampal-dependent tasks.

Primary pulmonary sarcoma in a rhesus monkey after inhalation of plutonium dioxide

International Nuclear Information System (INIS)

Hahn, F.F.; Brooks, A.L.; Mewhinney, J.A.

1987-01-01

A pulmonary fibrosarcoma of bronchial origin was discovered in a Rhesus monkey that died of pulmonary fibrosis 9 years after inhalation of plutonium-239 dioxide and with a radiation dose to lung of 1400 rad (14 Gy). It grew around the major bronchus of the right cardiac lung lobe and extended into the bronchial lumen and into surrounding pulmonary parenchyma. It also readily invaded muscular pulmonary arteries, resulting in infarction and scarring in the right cardiac lobe. Despite this aggressive growth, the tumor did not metastasize. The primary cause of death was severe pulmonary fibrosis involving the alveolar septa and and perivascular and peribronchial interstitium. Bullous or pericitrical emphysema was prominent. The initial lung burden of plutonium in this monkey was 270 nCi (10 kBq) which is equivalent to approximately 500 times the maximum permissible lung burden for man on a radioactivity per unit body weight basis. The time-dose relationship for survival is consistent with that of dogs and baboons that inhaled plutonium dioxide and died with lung tumors

Postpyloric regulation of gastric emptying in rhesus monkeys.

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McHugh, P R; Moran, T H; Wirth, J B

1982-09-01

Saline (0.9% NaCl) empties rapidly and exponentially from the stomach of the rhesus monkey, but glucose solutions empty at a calorie-constant rate of 0.4 kcal/min. By means of indwelling intragastric and intraduodenal cannulae we can demonstrate an inhibition on the delivery of saline from the stomach provoked by glucose placed beyond the pylorus. The inhibition varies directly with the glucose calories in the intestine and averages 2.5 min/kcal. That these two results (0.4 kcal/min and 2.5 min/kcal) are reciprocals suggests a feedback inhibition on the gastric emptying of nutrients arising from beyond the pylorus and adequate to explain the rate of glucose delivery to the intestine. A control theory description of gastric emptying that includes such feedback regulation can be derived from these data to explain the different gastric emptying patterns of nutrients and nonnutrient solutions. These patterns give this visceral system a precision in its management of nutrients that can provide information crucial to preabsorptive satiety.

Evaluation of the differences of myocardial fibers between acute and chronic myocardial infarction: Application of diffusion tensor magnetic resonance imaging INA Rhesus monkey model

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Wang, Yu Qing; Cai, Wei; Wang, Lei; Xia, Rui; Chen, Wei; Zheng, Jie [Dept. of Radiology, West China Hospital, Sichuan University, Sichuan (China); Gao, Fabao [Mallinckrodt Institute of Radiology, School of Medicine, Washington University, St. Louis (United States)

2016-09-15

To understand microstructural changes after myocardial infarction (MI), we evaluated myocardial fibers of rhesus monkeys during acute or chronic MI, and identified the differences of myocardial fibers between acute and chronic MI. Six fixed hearts of rhesus monkeys with left anterior descending coronary artery ligation for 1 hour or 84 days were scanned by diffusion tensor magnetic resonance imaging (MRI) to measure apparent diffusion coefficient (ADC), fractional anisotropy (FA) and helix angle (HA). Comparing with acute MI monkeys (FA: 0.59 ± 0.02; ADC: 5.0 ± 0.6 × 10{sup -4} mm{sup 2}/s; HA: 94.5 ± 4.4°), chronic MI monkeys showed remarkably decreased FA value (0.26 ± 0.03), increased ADC value (7.8 ± 0.8 × 10{sup -4} mm{sup 2}/s), decreased HA transmural range (49.5 ± 4.6°) and serious defects on endocardium in infarcted regions. The HA in infarcted regions shifted to more components of negative left-handed helix in chronic MI monkeys (-38.3 ± 5.0°–11.2 ± 4.3°) than in acute MI monkeys (-41.4 ± 5.1°–53.1 ± 3.7°), but the HA in remote regions shifted to more components of positive right-handed helix in chronic MI monkeys (-43.8 ± 2.7°–66.5 ± 4.9°) than in acute MI monkeys (-59.5 ± 3.4°–64.9 ± 4.3°). Diffusion tensor MRI method helps to quantify differences of mechanical microstructure and water diffusion of myocardial fibers between acute and chronic MI monkey's models.

Evaluation of the differences of myocardial fibers between acute and chronic myocardial infarction: Application of diffusion tensor magnetic resonance imaging INA Rhesus monkey model

International Nuclear Information System (INIS)

Wang, Yu Qing; Cai, Wei; Wang, Lei; Xia, Rui; Chen, Wei; Zheng, Jie; Gao, Fabao

2016-01-01

To understand microstructural changes after myocardial infarction (MI), we evaluated myocardial fibers of rhesus monkeys during acute or chronic MI, and identified the differences of myocardial fibers between acute and chronic MI. Six fixed hearts of rhesus monkeys with left anterior descending coronary artery ligation for 1 hour or 84 days were scanned by diffusion tensor magnetic resonance imaging (MRI) to measure apparent diffusion coefficient (ADC), fractional anisotropy (FA) and helix angle (HA). Comparing with acute MI monkeys (FA: 0.59 ± 0.02; ADC: 5.0 ± 0.6 × 10 -4 mm 2 /s; HA: 94.5 ± 4.4°), chronic MI monkeys showed remarkably decreased FA value (0.26 ± 0.03), increased ADC value (7.8 ± 0.8 × 10 -4 mm 2 /s), decreased HA transmural range (49.5 ± 4.6°) and serious defects on endocardium in infarcted regions. The HA in infarcted regions shifted to more components of negative left-handed helix in chronic MI monkeys (-38.3 ± 5.0°–11.2 ± 4.3°) than in acute MI monkeys (-41.4 ± 5.1°–53.1 ± 3.7°), but the HA in remote regions shifted to more components of positive right-handed helix in chronic MI monkeys (-43.8 ± 2.7°–66.5 ± 4.9°) than in acute MI monkeys (-59.5 ± 3.4°–64.9 ± 4.3°). Diffusion tensor MRI method helps to quantify differences of mechanical microstructure and water diffusion of myocardial fibers between acute and chronic MI monkey's models

Sleeve bridging of the rhesus monkey ulnar nerve with muscular branches of the pronator teres: multiple amplification of axonal regeneration

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Yu-hui Kou

2015-01-01

Full Text Available Multiple-bud regeneration, i.e., multiple amplification, has been shown to exist in peripheral nerve regeneration. Multiple buds grow towards the distal nerve stump during proximal nerve fiber regeneration. Our previous studies have verified the limit and validity of multiple amplification of peripheral nerve regeneration using small gap sleeve bridging of small donor nerves to repair large receptor nerves in rodents. The present study sought to observe multiple amplification of myelinated nerve fiber regeneration in the primate peripheral nerve. Rhesus monkey models of distal ulnar nerve defects were established and repaired using muscular branches of the right forearm pronator teres. Proximal muscular branches of the pronator teres were sutured into the distal ulnar nerve using the small gap sleeve bridging method. At 6 months after suture, two-finger flexion and mild wrist flexion were restored in the ulnar-sided injured limbs of rhesus monkey. Neurophysiological examination showed that motor nerve conduction velocity reached 22.63 ± 6.34 m/s on the affected side of rhesus monkey. Osmium tetroxide staining demonstrated that the number of myelinated nerve fibers was 1,657 ± 652 in the branches of pronator teres of donor, and 2,661 ± 843 in the repaired ulnar nerve. The rate of multiple amplification of regenerating myelinated nerve fibers was 1.61. These data showed that when muscular branches of the pronator teres were used to repair ulnar nerve in primates, effective regeneration was observed in regenerating nerve fibers, and functions of the injured ulnar nerve were restored to a certain extent. Moreover, multiple amplification was subsequently detected in ulnar nerve axons.

Sleeve bridging of the rhesus monkey ulnar nerve with muscular branches of the pronator teres: multiple amplification of axonal regeneration.

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Kou, Yu-Hui; Zhang, Pei-Xun; Wang, Yan-Hua; Chen, Bo; Han, Na; Xue, Feng; Zhang, Hong-Bo; Yin, Xiao-Feng; Jiang, Bao-Guo

2015-01-01

Multiple-bud regeneration, i.e., multiple amplification, has been shown to exist in peripheral nerve regeneration. Multiple buds grow towards the distal nerve stump during proximal nerve fiber regeneration. Our previous studies have verified the limit and validity of multiple amplification of peripheral nerve regeneration using small gap sleeve bridging of small donor nerves to repair large receptor nerves in rodents. The present study sought to observe multiple amplification of myelinated nerve fiber regeneration in the primate peripheral nerve. Rhesus monkey models of distal ulnar nerve defects were established and repaired using muscular branches of the right forearm pronator teres. Proximal muscular branches of the pronator teres were sutured into the distal ulnar nerve using the small gap sleeve bridging method. At 6 months after suture, two-finger flexion and mild wrist flexion were restored in the ulnar-sided injured limbs of rhesus monkey. Neurophysiological examination showed that motor nerve conduction velocity reached 22.63 ± 6.34 m/s on the affected side of rhesus monkey. Osmium tetroxide staining demonstrated that the number of myelinated nerve fibers was 1,657 ± 652 in the branches of pronator teres of donor, and 2,661 ± 843 in the repaired ulnar nerve. The rate of multiple amplification of regenerating myelinated nerve fibers was 1.61. These data showed that when muscular branches of the pronator teres were used to repair ulnar nerve in primates, effective regeneration was observed in regenerating nerve fibers, and functions of the injured ulnar nerve were restored to a certain extent. Moreover, multiple amplification was subsequently detected in ulnar nerve axons.

Exploring the extent and function of higher-order auditory cortex in rhesus monkeys.

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Poremba, Amy; Mishkin, Mortimer

2007-07-01

Just as cortical visual processing continues far beyond the boundaries of early visual areas, so too does cortical auditory processing continue far beyond the limits of early auditory areas. In passively listening rhesus monkeys examined with metabolic mapping techniques, cortical areas reactive to auditory stimulation were found to include the entire length of the superior temporal gyrus (STG) as well as several other regions within the temporal, parietal, and frontal lobes. Comparison of these widespread activations with those from an analogous study in vision supports the notion that audition, like vision, is served by several cortical processing streams, each specialized for analyzing a different aspect of sensory input, such as stimulus quality, location, or motion. Exploration with different classes of acoustic stimuli demonstrated that most portions of STG show greater activation on the right than on the left regardless of stimulus class. However, there is a striking shift to left-hemisphere "dominance" during passive listening to species-specific vocalizations, though this reverse asymmetry is observed only in the region of temporal pole. The mechanism for this left temporal pole "dominance" appears to be suppression of the right temporal pole by the left hemisphere, as demonstrated by a comparison of the results in normal monkeys with those in split-brain monkeys.

Control of viremia and prevention of AIDS following immunotherapy of SIV-infected macaques with peptide-pulsed blood.

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Robert De Rose

2008-05-01

Full Text Available Effective immunotherapies for HIV are needed. Drug therapies are life-long with significant toxicities. Dendritic-cell based immunotherapy approaches are promising but impractical for widespread use. A simple immunotherapy, reinfusing fresh autologous blood cells exposed to overlapping SIV peptides for 1 hour ex vivo, was assessed for the control of SIV(mac251 replication in 36 pigtail macaques. An initial set of four immunizations was administered under antiretroviral cover and a booster set of three immunizations administered 6 months later. Vaccinated animals were randomized to receive Gag peptides alone or peptides spanning all nine SIV proteins. High-level, SIV-specific CD4 and CD8 T-cell immunity was induced following immunization, both during antiretroviral cover and without. Virus levels were durably approximately 10-fold lower for 1 year in immunized animals compared to controls, and a significant delay in AIDS-related mortality resulted. Broader immunity resulted following immunizations with peptides spanning all nine SIV proteins, but the responses to Gag were weaker in comparison to animals only immunized with Gag. No difference in viral outcome occurred in animals immunized with all SIV proteins compared to animals immunized against Gag alone. Peptide-pulsed blood cells are an immunogenic and effective immunotherapy in SIV-infected macaques. Our results suggest Gag alone is an effective antigen for T-cell immunotherapy. Fresh blood cells pulsed with overlapping Gag peptides is proceeding into trials in HIV-infected humans.

Shallow discounting of delayed cocaine by male rhesus monkeys when immediate food is the choice alternative.

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Huskinson, Sally L; Myerson, Joel; Green, Leonard; Rowlett, James K; Woolverton, William L; Freeman, Kevin B

2016-12-01

Huskinson et al. (2015) recently examined delay discounting in monkeys choosing between an immediate drug (cocaine) reinforcer and a delayed nondrug (food) reinforcer. The present experiment examined the reverse situation: choice between immediate nondrug (food) and delayed drug (cocaine) reinforcers. Whereas the former choice situation exemplifies drug abuse from a delay-discounting perspective, our interest in the latter choice situation is derived from the observation that drug abusers, who characteristically are associated with impulsive choice, typically must devote considerable time to procuring drugs, often at the expense of immediate nondrug alternatives. Accordingly, we analyzed 3 male rhesus monkeys' choices between immediate food and delayed cocaine (0.1 and 0.2 mg/kg/injection) using a hyperbolic model that allowed us to compare discounting rates between qualitatively different reinforcers. Choice of immediate food increased with food amount, and choice functions generally shifted leftward as delay to cocaine increased, indicating a decrease in the subjective value of cocaine. Compared with our previous delay-discounting experiment with immediate cocaine versus delayed food, both doses of delayed cocaine were discounted at a shallow rate. The present results demonstrate that rhesus monkeys will tolerate relatively long delays in an immediate-food versus delayed-drug situation, suggesting that in intertemporal choices between cocaine and food, the subjective value of cocaine is less affected by the delay until reinforcement than is the subjective value of delayed food. More generally, the present findings suggest that although drug abusers may choose impulsively when immediate drug reinforcement is available, they exercise self-control in the acquisition of a highly preferred, delayed drug reinforcer. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

Minocycline Inhibition of Monocyte Activation Correlates with Neuronal Protection in SIV NeuroAIDS

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Campbell, Jennifer H.; Burdo, Tricia H.; Autissier, Patrick; Bombardier, Jeffrey P.; Westmoreland, Susan V.; Soulas, Caroline; González, R. Gilberto; Ratai, Eva-Maria; Williams, Kenneth C.

2011-01-01

Background Minocycline is a tetracycline antibiotic that has been proposed as a potential conjunctive therapy for HIV-1 associated cognitive disorders. Precise mechanism(s) of minocycline's functions are not well defined. Methods Fourteen rhesus macaques were SIV infected and neuronal metabolites measured by proton magnetic resonance spectroscopy (1H MRS). Seven received minocycline (4 mg/kg) daily starting at day 28 post-infection (pi). Monocyte expansion and activation were assessed by flow cytometry, cell traffic to lymph nodes, CD16 regulation, viral replication, and cytokine production were studied. Results Minocycline treatment decreased plasma virus and pro-inflammatory CD14+CD16+ and CD14loCD16+ monocytes, and reduced their expression of CD11b, CD163, CD64, CCR2 and HLA-DR. There was reduced recruitment of monocyte/macrophages and productively infected cells in axillary lymph nodes. There was an inverse correlation between brain NAA/Cr (neuronal injury) and circulating CD14+CD16+ and CD14loCD16+ monocytes. Minocycline treatment in vitro reduced SIV replication CD16 expression on activated CD14+CD16+ monocytes, and IL-6 production by monocytes following LPS stimulation. Conclusion Neuroprotective effects of minocycline are due in part to reduction of activated monocytes, monocyte traffic. Mechanisms for these effects include CD16 regulation, reduced viral replication, and inhibited immune activation. PMID:21494695

Remote and chronic access to the third cerebral ventricle of the unrestrained prepubertal rhesus monkey.

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Gay, V L; Mikuma, N; Plant, T M

1993-03-01

One channel of a commercially available standard-size three-channel fluid swivel was modified to permit continuous access to the brain of unrestrained prepubertal rhesus monkeys via a continuous length of small-bore Teflon tube originating from a swivel device on top of the animal's cage and terminating in the third cerebral ventricle. This system was employed to achieve continuous access to the third cerebroventricle in four monkeys for periods of up to 12 mo. The value of the system for studies of the neurochemical control of hypothalamic-releasing factor secretion was established by monitoring adenohypophysial responses to neurotransmitter receptor agonists infused into the third ventricle. Specifically, repetitive infusions of morphine (30 micrograms/infusion) elicited a robust train of prolactin discharges, and third ventricular administration of N-methyl-DL-aspartic acid (NMA; 20 micrograms) resulted in striking discharges of LH.

Rhesus monkey rhadinovirus (RRV): construction of a RRV-GFP recombinant virus and development of assays to assess viral replication

International Nuclear Information System (INIS)

DeWire, Scott M.; Money, Eric S.; Krall, Stuart P.; Damania, Blossom

2003-01-01

Rhesus monkey rhadinovirus (RRV) is a γ-2-herpesvirus that is closely related to Kaposi's sarcoma-associated herpesvirus (KSHV/HHV-8). Lack of an efficient culture system to grow high titers of virus, and the lack of an in vivo animal model system, has hampered the study of KSHV replication and pathogenesis. RRV is capable of replicating to high titers on fibroblasts, thus facilitating the construction of recombinant rhadinoviruses. In addition, the ability to experimentally infect naieve rhesus macaques with RRV makes it an excellent model system to study γ-herpesvirus replication. Our study describes, for the first time, the construction of a GFP-expressing RRV recombinant virus using a traditional homologous recombination strategy. We have also developed two new methods for determining viral titers of RRV including a traditional viral plaque assay and a quantitative real-time PCR assay. We have compared the replication of wild-type RRV with that of the RRV-GFP recombinant virus in one-step growth curves. We have also measured the sensitivity of RRV to a small panel of antiviral drugs. The development of both the recombination strategy and the viral quantitation assays for RRV will lay the foundation for future studies to evaluate the contribution of individual genes to viral replication both in vitro and in vivo

Repeated episodes of ozone inhalation amplifies the effects of allergen sensitization and inhalation on airway immune and structural development in Rhesus monkeys.

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Schelegle, Edward S; Miller, Lisa A; Gershwin, Laurel J; Fanucchi, Michelle V; Van Winkle, Laura S; Gerriets, Joan E; Walby, William F; Mitchell, Valerie; Tarkington, Brian K; Wong, Viviana J; Baker, Gregory L; Pantle, Lorraine M; Joad, Jesse P; Pinkerton, Kent E; Wu, Reen; Evans, Michael J; Hyde, Dallas M; Plopper, Charles G

2003-08-15

Twenty-four infant rhesus monkeys (30 days old) were exposed to 11 episodes of filtered air (FA), house dust mite allergen aerosol (HDMA), ozone (O3), or HDMA + O3 (5 days each followed by 9 days of FA). Ozone was delivered for 8 h/day at 0.5 ppm. Twelve of the monkeys were sensitized to house dust mite allergen (Dermatophagoides farinae) at ages 14 and 28 days by subcutaneous inoculation (SQ) of HDMA in alum and intraperitoneal injection of heat-killed Bordetella pertussis cells. Sensitized monkeys were exposed to HDMA aerosol for 2 h/day on days 3-5 of either FA (n = 6) or O3 (n = 6) exposure. Nonsensitized monkeys were exposed to either FA (n = 6) or O3 (n = 6). During the exposure regimen, parameters of allergy (i.e., serum IgE, histamine, and eosinophilia), airways resistance, reactivity, and structural remodeling were evaluated. Eleven repeated 5-day cycles of inhaling 0.5 ppm ozone over a 6-month period had only mild effects on the airways of nonsensitized infant rhesus monkeys. Similarly, the repeated inhalation of HDMA by HDMA-sensitized infant monkeys resulted in only mild airway effects, with the exception of a marked increase in proximal airway and terminal bronchiole content of eosinophils. In contrast, the combined cyclic inhalation of ozone and HDMA by HDMA sensitized infants monkeys resulted in a marked increase in serum IgE, serum histamine, and airways eosinophilia. Furthermore, combined cyclic inhalation of ozone and HDMA resulted in even greater alterations in airway structure and content that were associated with a significant elevation in baseline airways resistance and reactivity. These results suggest that ozone can amplify the allergic and structural remodeling effects of HDMA sensitization and inhalation.

Effects of chronic copper exposure during early life in rhesus monkeys.

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Araya, Magdalena; Kelleher, Shannon L; Arredondo, Miguel A; Sierralta, Walter; Vial, María Teresa; Uauy, Ricardo; Lönnerdal, Bo

2005-05-01

Whether infants regulate copper absorption and the potential effects of excess copper in early life remain poorly defined. The objective of the study was to assess copper retention, liver copper content, and liver function in infant rhesus monkeys fed infant formula containing 6.6 mg Cu/L. From birth to 5 mo of age, infant rhesus monkeys were fed formula that was supplemented with copper (0.6 mg Cu/L; n = 5) or not supplemented (n = 4). In all animals, weight and crown-rump length (by anthropometry), hemoglobin, hematocrit, plasma ceruloplasmin activity, and zinc and copper concentrations were measured monthly (birth to 6 mo) and at 8 and 12 mo. When the animals were 1, 5, and 8 mo old, liver copper and metallothionein concentrations, liver histology (by light and electron microscopy), and the number of Kupffer cells were assessed, and 67Cu retention was measured. Liver function was assessed by measurement of plasma alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, and alkaline phosphatase activities and protein, albumin, bilirubin, and blood urea nitrogen concentrations. 67Cu retention was 19.2% and 10.9% after 1 and 5 mo of copper treatment, respectively, compared with approximately 75% in controls at age 2 mo. At age 8 mo, 67Cu retention was 22.9% in copper-treated animals and 31.5% in controls. Liver histology remained normal by light microscopy, with mild ultrastructural signs of cell damage at 5 mo. Liver copper concentration was 4711, 1139, and 498 microg/g dry tissue at 1, 5, and 8 mo, respectively, in copper-treated animals and 250 microg/g at 2 mo in controls. Measurements could not be completed in all animals. No clinical evidence of copper toxicity was observed. Copper absorption was down-regulated; increases in liver copper content at ages 1 and 5 mo did not result in histologic damage. Ultrastructural changes at age 5 mo could signal early cellular damage.

Evaluation of the Differences of Myocardial Fibers between Acute and Chronic Myocardial Infarction: Application of Diffusion Tensor Magnetic Resonance Imaging in a Rhesus Monkey Model

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Wang, Yuqing [Department of Radiology, West China Hospital, Sichuan University, Sichuan 610041 (China); CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology of China, Beijing 100190 (China); Cai, Wei [Department of Radiology, West China Hospital, Sichuan University, Sichuan 610041 (China); Department of Radiology, Beijing Jishuitan Hospital, 4th Clinical Medical College of Peking University, Beijing 100035 (China); Wang, Lei [Department of Radiology, West China Hospital, Sichuan University, Sichuan 610041 (China); Xia, Rui [Department of Radiology, West China Hospital, Sichuan University, Sichuan 610041 (China); Department of Radiology, The First Affiliated Hospital, Chongqing Medical University, Chongqing 400016 (China); Chen, Wei [Department of Radiology, West China Hospital, Sichuan University, Sichuan 610041 (China); Department of Radiology, The First Affiliated Hospital of Kunming Medical University, Yunnan 650032 (China); Zheng, Jie [Mallinckrodt Institute of Radiology, School of Medicine, Washington University, St. Louis, MO 63110 (United States); Gao, Fabao [Department of Radiology, West China Hospital, Sichuan University, Sichuan 610041 (China)

2016-11-01

To understand microstructural changes after myocardial infarction (MI), we evaluated myocardial fibers of rhesus monkeys during acute or chronic MI, and identified the differences of myocardial fibers between acute and chronic MI. Six fixed hearts of rhesus monkeys with left anterior descending coronary artery ligation for 1 hour or 84 days were scanned by diffusion tensor magnetic resonance imaging (MRI) to measure apparent diffusion coefficient (ADC), fractional anisotropy (FA) and helix angle (HA). Comparing with acute MI monkeys (FA: 0.59 ± 0.02; ADC: 5.0 ± 0.6 × 10{sup -4} mm{sup 2}/s; HA: 94.5 ± 4.4°), chronic MI monkeys showed remarkably decreased FA value (0.26 ± 0.03), increased ADC value (7.8 ± 0.8 × 10{sup -4}mm{sup 2}/s), decreased HA transmural range (49.5 ± 4.6°) and serious defects on endocardium in infarcted regions. The HA in infarcted regions shifted to more components of negative left-handed helix in chronic MI monkeys (-38.3 ± 5.0°–11.2 ± 4.3°) than in acute MI monkeys (-41.4 ± 5.1°–53.1 ± 3.7°), but the HA in remote regions shifted to more components of positive right-handed helix in chronic MI monkeys (-43.8 ± 2.7°–66.5 ± 4.9°) than in acute MI monkeys (-59.5 ± 3.4°–64.9 ± 4.3°). Diffusion tensor MRI method helps to quantify differences of mechanical microstructure and water diffusion of myocardial fibers between acute and chronic MI monkey's models.

The archetype enhancer of simian virus 40 DNA is duplicated during virus growth in human cells and rhesus monkey kidney cells but not in green monkey kidney cells

International Nuclear Information System (INIS)

O'Neill, Frank J.; Greenlee, John E.; Carney, Helen

2003-01-01

Archetype SV40, obtained directly from its natural host, is characterized by a single 72-bp enhancer element. In contrast, SV40 grown in cell culture almost invariably exhibits partial or complete duplication of the enhancer region. This distinction has been considered important in studies of human tumor material, since SV40-associated tumor isolates have been described having a single enhancer region, suggesting natural infection as opposed to possible contamination by laboratory strains of virus. However, the behavior of archetypal SV40 in cultured cells has never been methodically studied. In this study we reengineered nonarchetypal 776-SV40 to contain a single 72-bp enhancer region and used this reengineered archetypal DNA to transfect a number of simian and human cell lines. SV40 DNA recovered from these cells was analyzed by restriction endonuclease analysis, PCR, and DNA sequencing. Reengineered archetype SV40 propagated in green monkey TC-7 or BSC-1 kidney cells remained without enhancer region duplication even after extensive serial virus passage. Archetype SV40 grown in all but one of the rhesus or human cell lines initially appeared exclusively archetypal. However, when virus from these cell types was transferred to green monkey cells, variants with partial enhancer duplication appeared after as little as a single passage. These findings suggest (1) that virus with a single 72-bp enhancer may persist in cultured cells of simian and human origin; (2) that variants with partially duplicated enhancer regions may arise within cell lines in quantities below limits of detection; (3) that these variants may enjoy a selective advantage in cell types other than those from which they arose (e.g., green monkey kidney cells); and (4) that certain cell lines may support a selective growth advantage for the variants without supporting their formation. Our data indicate that enhancer duplication may also occur in human as well as rhesus kidney cells. Thus, detection of

The Secretion of IL-22 from Mucosal NKp44+ NK Cells Is Associated with Microbial Translocation and Virus Infection in SIV/SHIV-Infected Chinese Macaques

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Wei Wang

2014-01-01

Full Text Available Microbial translocation (MT causes systemic immune activation in chronic human immunodeficiency virus (HIV infection. The role of a novel subtype of innate lymphoid cells, the NKp44+ NK cells, in HIV/simian immunodeficiency virus- (SIV- induced MT remains unknown. In this study, 12 simian-human immunodeficiency virus- (SHIV- infected macaques were chosen and split into two groups based on the MT level. Blood and Peripheral lymphoid tissue were sampled for flow cytometric analysis, viral load detection, and interleukin testing. Then, six naive Chinese macaques were used to determine the dynamics of cytokine secretion from mucosal NKp44+ NK cells in different phases of SIV infection. As a result, the degranulation capacity and IL-22 production of mucosal NKp44+ NK cells were associated with the MT level in the SHIV-infected macaques. And the number of mucosal NKp44+ NK cells and IL-22 secretion by these cells were lower in the chronic phase than in the early acute phase of SIV infection. The number of mucosal NKp44+ NK cells and interleukin-22 (IL-22 secretion by these cells increased before MT occurred. Therefore, we conclude that a decline in IL-22 production from mucosal NKp44+ NK cells induced by virus infection may be one of the causes of microbial translocation in HIV/SIV infection.

Establishment of a rhesus monkey model of chronic temporal lobe epilepsy using repetitive unilateral intra-amygdala kainic acid injections.

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Chi, Yajie; Wu, Bolin; Guan, Jianwei; Xiao, Kuntai; Lu, Ziming; Li, Xiao; Xu, Yuting; Xue, Shan; Xu, Qiang; Rao, Junhua; Guo, Yanwu

2017-09-01

Temporal lobe epilepsy (TLE) is a common type of acquired epilepsy refractory to medical treatment. As such, establishing animal models of this disease is critical to developing new and effective treatment modalities. Because of their small head size, rodents are not suitable for comprehensive electroencephalography (EEG) evaluation via scalp or subdural electrodes. Therefore, a larger primate model that closely recapitulates signs of TLE is needed; here we describe a rhesus monkey model resembling chronic TLE. Eight monkeys were divided into two groups: kainic acid (KA) group (n=6) and saline control group (n=2). Intra-amygdala KA injections were performed biweekly via an Ommaya device until obvious epileptiform discharges were recorded. Video-EEG recording was conducted intermittently throughout the experiment using both scalp and subdural electrodes. Brains were then analyzed for Nissl and glial fibrillary acid protein (GFAP) immunostaining. After 2-4 injections of KA (approximately 1.2-2.4mg, 0.12-0.24mg/kg), interictal epileptiform discharges (IEDs) were recorded in all KA-treated animals. Spontaneous recurrent seizures (SRSs) accompanied by symptoms mimicking temporal lobe absence (undetectable without EEG recording), but few mild motor signs, were recorded in 66.7% (four of six) KA-treated animals. Both IEDs and seizures indicated a primary epileptic zone in the right temporal region and contralateral discharges were later detected. Segmental pyramidal cell loss and gliosis were detected in the brain of a KA-treated monkey. Through a modified protocol of unilateral repetitive intra-amygdala KA injections, a rhesus monkey model with similar behavioral and brain electrical features as TLE was developed. Copyright © 2017 Elsevier Inc. All rights reserved.

A 4-channel 3 Tesla phased array receive coil for awake rhesus monkey fMRI and diffusion MRI experiments.

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Khachaturian, Mark Haig

2010-01-01

Awake monkey fMRI and diffusion MRI combined with conventional neuroscience techniques has the potential to study the structural and functional neural network. The majority of monkey fMRI and diffusion MRI experiments are performed with single coils which suffer from severe EPI distortions which limit resolution. By constructing phased array coils for monkey MRI studies, gains in SNR and anatomical accuracy (i.e., reduction of EPI distortions) can be achieved using parallel imaging. The major challenges associated with constructing phased array coils for monkeys are the variation in head size and space constraints. Here, we apply phased array technology to a 4-channel phased array coil capable of improving the resolution and image quality of full brain awake monkey fMRI and diffusion MRI experiments. The phased array coil is that can adapt to different rhesus monkey head sizes (ages 4-8) and fits in the limited space provided by monkey stereotactic equipment and provides SNR gains in primary visual cortex and anatomical accuracy in conjunction with parallel imaging and improves resolution in fMRI experiments by a factor of 2 (1.25 mm to 1.0 mm isotropic) and diffusion MRI experiments by a factor of 4 (1.5 mm to 0.9 mm isotropic).

X-ray induced translocations in premeiotic germ cells of monkeys

International Nuclear Information System (INIS)

Buul, P.P.W. van

1991-01-01

Induction of reciprocal translocations by various X-ray exposures was studied in spermatogonial stem cells of rhesus monkeys (Macaca mulatta) and stump-tailed Macaques (arctoides) by means of spermatocyte analysis many cell generations after irradiation. The yields of trans-locations recovered from irradiated stump-tailed macaques were lower than those observed in rhesus monkeys and represent in fact the lowest induction rates per Gy ever recorded for experimental mammals. In the rhesus monkey a humped dose-effect relationship was found with 1.a homo -geneous response with (pseudo-)linear kinetics below 1 Gy, 2.much more variability at higher doses, and 3.no induction at all at doses of 4 Gy and above. It is suggested that the post-irradiation proliferation differentiation pattern of surviving rhesus monkey spermatogonial stem cells is mainly responsible for these characteristics of the dose-response curve. (author). 41 refs.; 1 fig.; 4 tabs

Metabolism in vitro 3H-testosterone in testis, epididymis and sex accessories of the rhesus monkey

International Nuclear Information System (INIS)

Arora-Dinkar, Renu; Dinakar, N.; Prasad, M.R.N.

1977-01-01

Metabolism of 3 H-testosterone in the reproductive organs of intact, castrated and cyproterone acetate treated rhesus monkeys was studied in vitro. The main androgen metabolite in the epididymis, ductus deferens, seminal vesicles, prostate and bulb-urethral glands of the intact monkeys was 5-α-dihydrotestosterone (DHT). Testosterone was not metabolized in slices of the testis, indicating very little 5-α-reductase activity in this organ. Bilateral castration caused a decrease in the metabolism of 3 H-testosterone in all tissues studied. The decrease was greater in the caput than in the corpus and cauda epididymides. Treatment with cyproterone acetate did not affect the formation of DHT in the ductus deferens and accessory glands. Azoospermia, following administration of cyproterone acetate, had little effect on the metabolism of 3 H-testosterone in the corpus and cauda epididymides; however, in the caput region the extent of formation of DHT was markedly reduced. These results are discussed in relation to the influence of spermatozoa, testicular fluid and testicular and peripheral androgens on the metabolism of 3 H-testosterone in epididymis of the monkey. (author)

Effects of the Monoamine Uptake Inhibitors RTI-112 and RTI-113 on Cocaine- and Food-Maintained Responding in Rhesus Monkeys

Science.gov (United States)

SS, Negus; NK, Mello; HL, Kimmel; LL, Howell; FI, Carroll

2009-01-01

Cocaine blocks uptake of the monoamines dopamine, serotonin and norepinephrine, and monoamine uptake inhibitors constitute one class of drugs under consideration as candidate “agonist” medications for the treatment of cocaine abuse and dependence. The pharmacological selectivity of monoamine uptake inhibitors to block uptake of dopamine, serotonin and norepinephrine is one factor that may influence the efficacy and/or safety of these compounds as drug abuse treatment medications. To address this issue, the present study compared the effects of 7-day treatment with a non-selective monoamine uptake inhibitor (RTI-112) and a dopamine-selective uptake inhibitor (RTI-113) on cocaine- and food-maintained responding in rhesus monkeys. Monkeys (N=3) were trained to respond for cocaine injections (0.01 mg/kg/inj) and food pellets under a second-order schedule [FR2(VR16:S)] during alternating daily components of cocaine and food availability. Both RTI-112 (0.0032–0.01 mg/kg/hr) and RTI-113 (0.01–0.056 mg/kg/hr) produced dose-dependent, sustained and nearly complete elimination of cocaine self-administration. However, for both drugs, the potency to reduce cocaine self-administration was similar to the potency to reduce food-maintained responding. These findings do not support the hypothesis that pharmacological selectivity to block dopamine uptake is associated with behavioral selectivity to decrease cocaine- vs. food-maintained responding in rhesus monkeys. PMID:18755212

Vaginal challenge with an SIV-based dual reporter system reveals that infection can occur throughout the upper and lower female reproductive tract.

Science.gov (United States)

Stieh, Daniel J; Maric, Danijela; Kelley, Z L; Anderson, Meegan R; Hattaway, Holly Z; Beilfuss, Beth A; Rothwangl, Katharina B; Veazey, Ronald S; Hope, Thomas J

2014-10-01

The majority of new HIV infections occur in women as a result of heterosexual intercourse, overcoming multiple innate barriers to infection within the mucosa. However, the avenues through which infection is established, and the nature of bottlenecks to transmission, have been the source of considerable investigation and contention. Using a high dose of a single round non-replicating SIV-based vector containing a novel dual reporter system, we determined the sites of infection by the inoculum using the rhesus macaque vaginal transmission model. Here we show that the entire female reproductive tract (FRT), including the vagina, ecto- and endocervix, along with ovaries and local draining lymph nodes can contain transduced cells only 48 hours after inoculation. The distribution of infection shows that virions quickly disseminate after exposure and can access target cells throughout the FRT, with an apparent preference for infection in squamous vaginal and ectocervical mucosa. JRFL enveloped virions infect diverse CD4 expressing cell types, with T cells resident throughout the FRT representing the primary target. These findings establish a new perspective that the entire FRT is susceptible and virus can reach as far as the ovary and local draining lymph nodes. Based on these findings, it is essential that protective mechanisms for prevention of HIV acquisition must be present at protective levels throughout the entire FRT to provide complete protection.

Recovery of behavioral symptoms in hemi-parkinsonian rhesus monkeys through combined gene and stem cell therapy.

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Zhou, Yan; Sun, Maosheng; Li, Hongjun; Yan, Min; He, Zhanlong; Wang, Wenju; Wang, Wanpu; Lu, Shuaiyao

2013-04-01

The use of adipose mesenchymal stromal cells (ASCs) in cellular and genic therapy has attracted considerable attention as a possible treatment for neurodegenerative disorders, including Parkinson disease. However, the effects of gene therapy combined with intracerebral cell transplantation have not been well defined. Recent studies have demonstrated the respective roles of LIM homeobox transcription factor 1, alpha (LMX1A) and Neurturin (NTN) in the commitment of embryonic stem cells (ESCs) to a midbrain dopaminergic neuronal fate and the commitment of mesenchymal stromal cells to cells supporting the nutrition and protection of neurons. We investigated a novel in vitro neuronal differentiation strategy with the use of LMX1A and Neurturin. We were able to elicit a neural phenotype regarding cell morphology, specific gene/protein expression and physiological function. Neuronal-primed ASCs derived from rhesus monkey (rASCs) combined with adenovirus containing NTN and tyrosine hydroxylase (TH) (Ad-NTN-TH) were implanted into the striatum and substantia nigra of methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-lesioned hemi-parkinsonian rhesus monkeys. Monkeys were monitored with the use of behavioral tests and health measures until the fourth month after implantation. The differentiated cells transcribed and expressed a variety of dopaminergic neuron-specific genes involved in the SHH/LMX1A pathway. Single-photon emission computed tomography analysis and postmortem analysis revealed that the grafting of rASCs combined with Ad-NTN-TH had neuroprotective effects compared with Ad-NTN-TH or rASCs alone. Behavioral measures demonstrated autograft survival and symptom amelioration. These findings may lead to cellular sources for autologous transplantation of Parkinson disease. Combined transplantation of Ad-NTN-TH and induced rASCs expressing LMX1A and NTN may be a better therapy candidate for the treatment of Parkinson disease. Copyright © 2013 International Society

Induction of Th1-Biased T Follicular Helper (Tfh) Cells in Lymphoid Tissues during Chronic Simian Immunodeficiency Virus Infection Defines Functionally Distinct Germinal Center Tfh Cells.

Science.gov (United States)

Velu, Vijayakumar; Mylvaganam, Geetha Hanna; Gangadhara, Sailaja; Hong, Jung Joo; Iyer, Smita S; Gumber, Sanjeev; Ibegbu, Chris C; Villinger, Francois; Amara, Rama Rao

2016-09-01

Chronic HIV infection is associated with accumulation of germinal center (GC) T follicular helper (Tfh) cells in the lymphoid tissue. The GC Tfh cells can be heterogeneous based on the expression of chemokine receptors associated with T helper lineages, such as CXCR3 (Th1), CCR4 (Th2), and CCR6 (Th17). However, the heterogeneous nature of GC Tfh cells in the lymphoid tissue and its association with viral persistence and Ab production during chronic SIV/HIV infection are not known. To address this, we characterized the expression of CXCR3, CCR4, and CCR6 on GC Tfh cells in lymph nodes following SIVmac251 infection in rhesus macaques. In SIV-naive rhesus macaques, only a small fraction of GC Tfh cells expressed CXCR3, CCR4, and CCR6. However, during chronic SIV infection, the majority of GC Tfh cells expressed CXCR3, whereas the proportion of CCR4(+) cells did not change, and CCR6(+) cells decreased. CXCR3(+), but not CXCR3(-), GC Tfh cells produced IFN-γ (Th1 cytokine) and IL-21 (Tfh cytokine), whereas both subsets expressed CD40L following stimulation. Immunohistochemistry analysis demonstrated an accumulation of CD4(+)IFN-γ(+) T cells within the hyperplastic follicles during chronic SIV infection. CXCR3(+) GC Tfh cells also expressed higher levels of ICOS, CCR5, and α4β7 and contained more copies of SIV DNA compared with CXCR3(-) GC Tfh cells. However, CXCR3(+) and CXCR3(-) GC Tfh cells delivered help to B cells in vitro for production of IgG. These data demonstrate that chronic SIV infection promotes expansion of Th1-biased GC Tfh cells, which are phenotypically and functionally distinct from conventional GC Tfh cells and contribute to hypergammaglobulinemia and viral reservoirs. Copyright © 2016 by The American Association of Immunologists, Inc.

Preclinical evaluation of a urokinase plasminogen activator receptor-targeted nanoprobe in rhesus monkeys

Directory of Open Access Journals (Sweden)

Chen Y

2015-10-01

Full Text Available Yushu Chen,1 Li Gong,2 Ning Gao,3 Jichun Liao,1 Jiayu Sun,1 Yuqing Wang,1 Lei Wang,1 Pengjin Zhu,1 Qing Fan,1 Yongqiang Andrew Wang,4 Wen Zeng,2 Hui Mao,3 Lily Yang,5 Fabao Gao11Molecular Imaging Center, Department of Radiology, West China Hospital, Sichuan University, Chengdu, 2Sichuan Primed Bio-Tech Group Co, Ltd, Chengdu, People’s Republic of China; 3Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, GA, 4Ocean NanoTech, LLC, San Diego, CA, 5Department of Surgery, Emory University School of Medicine, Atlanta, GA, USAPurpose: To translate a recombinant peptide containing the amino-terminal fragment (ATF of urokinase plasminogen activator receptor-targeted magnetic iron oxide (IO nanoparticles (uPAR-targeted human ATF-IONPs into clinical applications, we conducted a pilot study to evaluate the toxicity and pharmacokinetics of this nanoparticle in normal rhesus monkeys.Methods: We assessed the changes in the following: magnetic resonance imaging (MRI signals from pretreatment stage to 14 days posttreatment, serum iron concentrations from 5 minutes posttreatment to 12 weeks posttreatment, routine blood examination and serum chemistry analysis results from pretreatment stage to 12 weeks after administration, and results of staining of the liver with Perls’ Prussian Blue and hematoxylin–eosin at 24 hours and 3 months posttreatment in two rhesus monkeys following an intravenous administration of the targeted nanoparticles either with a polyethylene glycol (ATF-PEG-IONP or without a PEG (ATF-IONP coating.Results: The levels of alkaline phosphatase, alanine transaminase, and direct bilirubin in the two monkeys increased immediately after the administration of the IONPs but returned to normal within 20 days and stayed within the normal reference range 3 months after the injection. The creatinine levels of the two monkeys stayed within the normal range during the study. In addition, red blood cells

Crystallization and preliminary X-ray crystallographic analysis of the rhesus macaque MHC class I molecule Mamu-B*17 complexed with an immunodominant SIVmac239 Env epitope

International Nuclear Information System (INIS)

Gao, Feng; Bao, Jinku

2013-01-01

A primitive monoclinic crystal of the rhesus macaque MHC class I molecule Mamu-B*17 complexed with an SIVmac239 Env peptide was obtained and belonged to space group P2, with unit-cell parameters a = 68.3, b = 45.0, c = 81.5 Å, β = 96.5°. The crystal diffracted to 2.55 Å resolution. Long-term nonprogression during simian immunodeficiency virus (SIV) infection has been strongly associated with the major histocompatibility complex (MHC) class I allele Mamu-B*17. Here, a complex of rhesus macaque Mamu-B*17 with rhesus macaque β 2 -microglobulin (β 2 m) and an immunodominant peptide (SIVmac239 Env241–251; LRCNDTNYSGF; Env LF11) derived from the SIV Env protein was crystallized by the hanging-drop method using PEG 3350 as a precipitating agent. The crystals belonged to the primitive monoclinic space group P2, with unit-cell parameters a = 68.3, b = 45.0, c = 81.5 Å, β = 96.5°. Assuming the presence of one molecule in the asymmetric unit, the Matthews coefficient and solvent content were calculated to be 2.96 Å 3 Da −1 and 58.5%, respectively

Simple Mathematical Models Do Not Accurately Predict Early SIV Dynamics

Directory of Open Access Journals (Sweden)

Cecilia Noecker

2015-03-01

dose. These results suggest that, in order to appropriately model early HIV/SIV dynamics, additional factors must be considered in the model development. These may include variability in monkey susceptibility to infection, within-host competition between different viruses for target cells at the initial site of virus replication in the mucosa, innate immune response, and possibly the inclusion of several different tissue compartments. The sobering news is that while an increase in model complexity is needed to explain the available experimental data, testing and rejection of more complex models may require more quantitative data than is currently available.

Oral administration of live Shigella vaccine candidates in rhesus monkeys show no evidence of competition for colonization and immunogenicity between different serotypes.

Science.gov (United States)

Ranallo, R T; Kaminski, R; Baqar, S; Dutta, M; Lugo-Roman, L A; Boren, T; Barnoy, S; Venkatesan, M M

2014-03-26

Live oral monovalent Shigella flexneri 2a vaccine candidates as well as bivalent formulations with Shigella sonnei were evaluated in a rhesus monkey model for colonization and immunogenicity. Freshly harvested suspensions of S. flexneri 2a vaccine candidates WRSf2G12 and WRSf2G15 as well as S. sonnei vaccine candidate WRSs3 were nasogastrically administered to groups of rhesus monkeys, Macaca mulatta, either in a monovalent form or when combined with each other. The animals were monitored daily for physical well-being, stools were subjected to quantitative colony immunoblot assays for bacterial excretion and blood and stools were evaluated for humoral and mucosal immune responses. No clinical symptoms were noted in any group of animals and the vaccine candidates were excreted robustly for 48-72h without significant changes in either the magnitude or duration of excretion when given as a monovalent or as bivalent mixtures. Similarly, immunological interferences were not apparent in the magnitude of humoral and mucosal immune responses observed toward Shigella-specific antigens when monkeys were fed monovalent or bivalent formulations. These results predict that a multivalent live oral vaccine of more than one serotype can have a favorable outcome for protection against shigellosis. Published by Elsevier Ltd.

Chronic Binge Alcohol Administration Dysregulates Hippocampal Genes Involved in Immunity and Neurogenesis in Simian Immunodeficiency Virus-Infected Macaques

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John K. Maxi

2016-11-01

Full Text Available Alcohol use disorders (AUD exacerbate neurocognitive dysfunction in Human Immunodeficiency Virus (HIV+ patients. We have shown that chronic binge alcohol (CBA administration (13–14 g EtOH/kg/wk prior to and during simian immunodeficiency virus (SIV infection in rhesus macaques unmasks learning deficits in operant learning and memory tasks. The underlying mechanisms of neurocognitive alterations due to alcohol and SIV are not known. This exploratory study examined the CBA-induced differential expression of hippocampal genes in SIV-infected (CBA/SIV+; n = 2 macaques in contrast to those of sucrose administered, SIV-infected (SUC/SIV+; n = 2 macaques. Transcriptomes of hippocampal samples dissected from brains obtained at necropsy (16 months post-SIV inoculation were analyzed to determine differentially expressed genes. MetaCore from Thomson Reuters revealed enrichment of genes involved in inflammation, immune responses, and neurodevelopment. Functional relevance of these alterations was examined in vitro by exposing murine neural progenitor cells (NPCs to ethanol (EtOH and HIV trans-activator of transcription (Tat protein. EtOH impaired NPC differentiation as indicated by decreased βIII tubulin expression. These findings suggest a role for neuroinflammation and neurogenesis in CBA/SIV neuropathogenesis and warrant further investigation of their potential contribution to CBA-mediated neurobehavioral deficits.

Identification of SIV Nef CD8(+) T cell epitopes restricted by a MHC class I haplotype associated with lower viral loads in a macaque AIDS model.

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Nomura, Takushi; Yamamoto, Hiroyuki; Takahashi, Naofumi; Naruse, Taeko K; Kimura, Akinori; Matano, Tetsuro

2014-07-25

Virus-specific CD8(+) T-cell responses are crucial for the control of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) replication. Multiple studies on HIV-infected individuals and SIV-infected macaques have indicated association of several major histocompatibility complex class I (MHC-I) genotypes with lower viral loads and delayed AIDS progression. Understanding of the viral control mechanism associated with these MHC-I genotypes would contribute to the development of intervention strategy for HIV control. We have previously reported a rhesus MHC-I haplotype, 90-120-Ia, associated with lower viral loads after SIVmac239 infection. Gag206-216 and Gag241-249 epitope-specific CD8(+) T-cell responses have been shown to play a central role in the reduction of viral loads, whereas the effect of Nef-specific CD8(+) T-cell responses induced in all the 90-120-Ia(+) macaques on SIV replication remains unknown. Here, we identified three CD8(+) T-cell epitopes, Nef9-19, Nef89-97, and Nef193-203, associated with 90-120-Ia. Nef9-19 and Nef193-203 epitope-specific CD8(+) T-cell responses frequently selected for mutations resulting in viral escape from recognition by these CD8(+) T cells, indicating that these CD8(+) T cells exert strong suppressive pressure on SIV replication. Results would be useful for elucidation of the viral control mechanism associated with 90-120-Ia. Copyright © 2014 Elsevier Inc. All rights reserved.

Lack of clinical AIDS in SIV-infected sooty mangabeys with significant CD4+ T cell loss is associated with double-negative T cells

Science.gov (United States)

Milush, Jeffrey M.; Mir, Kiran D.; Sundaravaradan, Vasudha; Gordon, Shari N.; Engram, Jessica; Cano, Christopher A.; Reeves, Jacqueline D.; Anton, Elizabeth; O’Neill, Eduardo; Butler, Eboneé; Hancock, Kathy; Cole, Kelly S.; Brenchley, Jason M.; Else, James G.; Silvestri, Guido; Sodora, Donald L.

2011-01-01

SIV infection of natural host species such as sooty mangabeys results in high viral replication without clinical signs of simian AIDS. Studying such infections is useful for identifying immunologic parameters that lead to AIDS in HIV-infected patients. Here we have demonstrated that acute, SIV-induced CD4+ T cell depletion in sooty mangabeys does not result in immune dysfunction and progression to simian AIDS and that a population of CD3+CD4–CD8– T cells (double-negative T cells) partially compensates for CD4+ T cell function in these animals. Passaging plasma from an SIV-infected sooty mangabey with very few CD4+ T cells to SIV-negative animals resulted in rapid loss of CD4+ T cells. Nonetheless, all sooty mangabeys generated SIV-specific antibody and T cell responses and maintained normal levels of plasma lipopolysaccharide. Moreover, all CD4-low sooty mangabeys elicited a de novo immune response following influenza vaccination. Such preserved immune responses as well as the low levels of immune activation observed in these animals were associated with the presence of double-negative T cells capable of producing Th1, Th2, and Th17 cytokines. These studies indicate that SIV-infected sooty mangabeys do not appear to rely entirely on CD4+ T cells to maintain immunity and identify double-negative T cells as a potential subset of cells capable of performing CD4+ T cell–like helper functions upon SIV-induced CD4+ T cell depletion in this species. PMID:21317533

Evaluation of an intragastric challenge model for Shigella dysenteriae 1 in rhesus monkeys (Macaca mulatta) for the pre-clinical assessment of Shigella vaccine formulations

OpenAIRE

Islam, Dilara; Ruamsap, Nattaya; Khantapura, Patchariya; Aksomboon, Ajchara; Srijan, Apichai; Wongstitwilairoong, Boonchai; Bodhidatta, Ladaporn; Gettayacamin, Montip; Venkatesan, Malabi M; Mason, Carl J

2013-01-01

Shigellosis is a worldwide disease, characterized by abdominal pain, fever, vomiting, and the passage of blood- and mucus-streaked stools. Rhesus monkeys and other primates are the only animals that are naturally susceptible to shigellosis. A suitable animal model is required for the pre-clinical evaluation of vaccines candidates. In this study, the minimal dose of Shigella dysenteriae1 1617 strain required to produce dysentery in four of five (80% attack rate) monkeys using an escalating dos...

Small particle aerosol inoculation of cowpox Brighton Red in rhesus monkeys results in a severe respiratory disease

Energy Technology Data Exchange (ETDEWEB)

Johnson, Reed F. [Emerging Viral Pathogens Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, MD 21702 (United States); Hammoud, Dima A. [Center for Infectious Disease Imaging, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD 20892 (United States); Lackemeyer, Matthew G.; Yellayi, Srikanth [Integrated Research Facility, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, MD 21702 (United States); Solomon, Jeffrey [Center for Infectious Disease Imaging, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD 20892 (United States); Bohannon, Jordan K.; Janosko, Krisztina B.; Jett, Catherine; Cooper, Kurt [Integrated Research Facility, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, MD 21702 (United States); Blaney, Joseph E. [Office of the Scientific Director, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892 (United States); Jahrling, Peter B. [Emerging Viral Pathogens Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, MD 21702 (United States); Integrated Research Facility, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, MD 21702 (United States)

2015-07-15

Cowpox virus (CPXV) inoculation of nonhuman primates (NHPs) has been suggested as an alternate model for smallpox (Kramski et al., 2010, PLoS One, 5, e10412). Previously, we have demonstrated that intrabronchial inoculation of CPXV-Brighton Red (CPXV-BR) into cynomolgus monkeys resulted in a disease that shared many similarities to smallpox; however, severe respiratory tract disease was observed (Smith et al., 2011, J. Gen. Virol.). Here we describe the course of disease after small particle aerosol exposure of rhesus monkeys using computed tomography (CT) to monitor respiratory disease progression. Subjects developed a severe respiratory disease that was uniformly lethal at 5.7 log{sub 10} PFU of CPXV-BR. CT indicated changes in lung architecture that correlated with changes in peripheral blood monocytes and peripheral oxygen saturation. While the small particle aerosol inoculation route does not accurately mimic human smallpox, the data suggest that CT can be used as a tool to monitor real-time disease progression for evaluation of animal models for human diseases. - Highlights: • Small particle aerosol exposure of rhesus results in a severe respiratory disease. • CT findings correlated with peripheral oxygen saturation and monocyte increases. • Virus dissemination was limited and mainly confined to the respiratory tract. • CT provides insight into pathogenesis to aid development of animal models of disease.

Small particle aerosol inoculation of cowpox Brighton Red in rhesus monkeys results in a severe respiratory disease

International Nuclear Information System (INIS)

Johnson, Reed F.; Hammoud, Dima A.; Lackemeyer, Matthew G.; Yellayi, Srikanth; Solomon, Jeffrey; Bohannon, Jordan K.; Janosko, Krisztina B.; Jett, Catherine; Cooper, Kurt; Blaney, Joseph E.; Jahrling, Peter B.

2015-01-01

Cowpox virus (CPXV) inoculation of nonhuman primates (NHPs) has been suggested as an alternate model for smallpox (Kramski et al., 2010, PLoS One, 5, e10412). Previously, we have demonstrated that intrabronchial inoculation of CPXV-Brighton Red (CPXV-BR) into cynomolgus monkeys resulted in a disease that shared many similarities to smallpox; however, severe respiratory tract disease was observed (Smith et al., 2011, J. Gen. Virol.). Here we describe the course of disease after small particle aerosol exposure of rhesus monkeys using computed tomography (CT) to monitor respiratory disease progression. Subjects developed a severe respiratory disease that was uniformly lethal at 5.7 log 10 PFU of CPXV-BR. CT indicated changes in lung architecture that correlated with changes in peripheral blood monocytes and peripheral oxygen saturation. While the small particle aerosol inoculation route does not accurately mimic human smallpox, the data suggest that CT can be used as a tool to monitor real-time disease progression for evaluation of animal models for human diseases. - Highlights: • Small particle aerosol exposure of rhesus results in a severe respiratory disease. • CT findings correlated with peripheral oxygen saturation and monocyte increases. • Virus dissemination was limited and mainly confined to the respiratory tract. • CT provides insight into pathogenesis to aid development of animal models of disease

What meaning means for same and different: Analogical reasoning in humans (Homo sapiens), chimpanzees (Pan troglodytes), and rhesus monkeys (Macaca mulatta).

Science.gov (United States)

Flemming, Timothy M; Beran, Michael J; Thompson, Roger K R; Kleider, Heather M; Washburn, David A

2008-05-01

Thus far, language- and token-trained apes (e.g., D. Premack, 1976; R. K. R. Thompson, D. L. Oden, & S. T. Boysen, 1997) have provided the best evidence that nonhuman animals can solve, complete, and construct analogies, thus implicating symbolic representation as the mechanism enabling the phenomenon. In this study, the authors examined the role of stimulus meaning in the analogical reasoning abilities of three different primate species. Humans (Homo sapiens), chimpanzees (Pan troglodytes), and rhesus monkeys (Macaca mulatta) completed the same relational matching-to-sample (RMTS) tasks with both meaningful and nonmeaningful stimuli. This discrimination of relations-between-relations serves as the basis for analogical reasoning. Meaningfulness facilitated the acquisition of analogical matching for human participants, whereas individual differences among the chimpanzees suggest that meaning can either enable or hinder their ability to complete analogies. Rhesus monkeys did not succeed in the RMTS task regardless of stimulus meaning, suggesting that their ability to reason analogically, if present at all, may be dependent on a dimension other than the representational value of stimuli. PsycINFO Database Record (c) 2008 APA, all rights reserved.

Upregulation of Aβ42 in the Brain and Bodily Fluids of Rhesus Monkeys with Aging.

Science.gov (United States)

Zhao, Qiao; Lu, Jing; Yao, Zitong; Wang, Shubo; Zhu, Liming; Wang, Ju; Chen, Baian

2017-01-01

The cerebral accumulation of amyloid beta (Aβ) is one of the key pathological hallmarks of Alzheimer's disease (AD). Aβ is also found in bodily fluids such as the cerebrospinal fluid (CSF) and plasma. However, the significance of Aβ accumulation in the brain and different bodily pools, as well as its correlation with aging and cerebral amyloid pathology, is not completely understood. To better understand this question, we selected the rhesus monkey, which is phylogenetically and physiologically highly similar to the human, as a model to study. We quantified the levels of the two main Aβ isoforms (Aβ42 and Aβ40) in different sections of the brain (frontal cortex, temporal cortex, and hippocampus) and bodily fluids (CSF and plasma) of rhesus monkeys at different developmental phases (young, 5-9 years of age; mature, 10-19 years of age; and old, 21-24 years of age). We found that the levels of neuronal and insoluble Aβ42 increased significantly in the brain with aging, suggesting that this specific isoform might be directly involved in aging and AD-like pathophysiology. There was no significant change in the Aβ40 level in the brain with aging. In addition, the Aβ42 level, but not the Aβ40 level, in both the CSF and plasma increased with aging. We also identified a positive correlation between Aβ42 in the CSF and plasma and Aβ42 in the brain. Taken collectively, our results indicate that there is an association between Aβ accumulation and age. These results support the increased incidence of AD with aging.

Expression, purification, crystallization and preliminary X-ray diffraction analysis of rhesus macaque CD8αα homodimer

International Nuclear Information System (INIS)

Zong, Lili; Chen, Yong; Yan, Jinghua; Zhang, Jianhua

2010-01-01

CD8α exodomain protein, a crucial immune-system factor in rhesus macaque (M. mulatta), one of the best animal models for vaccine design, was assembled and crystallized. The full structure data will contribute to future studies of immune responses in rhesus macaques. As a T-cell co-receptor, CD8 binds to MHC class I molecules and plays a pivotal role in the activation of cytotoxic T lymphocytes. To date, structures of CD8 have been solved for two different mammals: human and mouse. The infection of rhesus macaques (Macaca mulatta) by simian immunodeficiency virus (SIV) is the best animal model for studying HIV. In this study, the rhesus macaque CD8 (rCD8) αα homodimer was obtained and rCD8α exodomain protein crystals were successfully obtained for further structural analysis. Diffraction data were collected to a resolution of 2.4 Å. The crystal belonged to space group P2 1 2 1 2 1 , with unit-cell parameters a = 46.52, b = 56.28, c = 82.40 Å. These data will facilitate further studies on the structural differences between these CD8 structures and the cellular immune responses of rhesus macaque

Shigella flexneri infection in a newly acquired rhesus macaque (Macaca mulatta)

OpenAIRE

Lee, Jae-Il; Kim, Sang-Joon; Park, Chung-Gyu

2011-01-01

A 3.4 year-old rhesus macaque weighing 4.5 kg, was suffering from anorexia, acute mucous and bloody diarrhea. On physical examination, the monkey showed a loss of activity, hunched posture, abdominal pain, dehydration, mild gingivitis and unclean anus with discharge. Whole blood was collected for the examination of electrolytes, hematology and serum chemistry; fresh stool was also collected for bacterial culture. Blood profiles showed leukocytosis (14.5 K/?L) and neutrophilia (11.0 K/?L) on c...

Comparative evaluation of oral and intranasal priming with replication-competent adenovirus 5 host range mutant (Ad5hr)-simian immunodeficiency virus (SIV) recombinant vaccines on immunogenicity and protective efficacy against SIV(mac251).

Science.gov (United States)

Zhou, Qifeng; Hidajat, Rachmat; Peng, Bo; Venzon, David; Aldrich, M Kristine; Richardson, Ersell; Lee, Eun Mi; Kalyanaraman, V S; Grimes, George; Gómez-Román, V Raúl; Summers, L Ebonita; Malkevich, Nina; Robert-Guroff, Marjorie

2007-11-19

Oral, replication-competent Ad-HIV vaccines are advancing to human trials. Previous evaluation of protective efficacy in non-human primates has primarily followed upper respiratory tract administrations. Here we compared sequential oral (O/O) versus intranasal/oral (I/O) priming of rhesus macaques with Ad5 host range mutant-SIV recombinants expressing SIV env/rev, gag, and nef genes followed by boosting with SIV gp120 protein. Cellular immune responses in PBMC were stronger and more frequent after I/O administration. Both groups developed mucosal immunity, including memory cells in bronchial alveolar lavage, and gut-homing receptors on PBMC. Following intrarectal SIV(mac251) challenge, both groups exhibited equivalent, significant protection and robust post-challenge cellular immunity. Our results illustrate the promise of oral replication-competent Ad-recombinant vaccines. Pre-challenge PBMC ELISPOT and proliferative responses did not predict protection in the O/O group, highlighting the need for simple, non-invasive methods to reliably assess mucosal immunity.

Mucosal vaccination with heterologous viral vectored vaccine targeting subdominant SIV accessory antigens strongly inhibits early viral replication

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Xu, Huanbin; Andersson, Anne-Marie Carola; Ragonnaud, Emeline

2017-01-01

Conventional HIV T cell vaccine strategies have not been successful in containing acute peak viremia, nor in providing long-term control. We immunized rhesus macaques intramuscularly and rectally using a heterologous adenovirus vectored SIV vaccine regimen encoding normally weakly immunogenic tat...

SIVdrl detection in captive mandrills: are mandrills infected with a third strain of simian immunodeficiency virus?

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Osterhaus Albert DME

2004-11-01

Full Text Available Abstract A pol-fragment of simian immunodeficiency virus (SIV that is highly related to SIVdrl-pol from drill monkeys (Mandrillus leucophaeus was detected in two mandrills (Mandrillus sphinx from Amsterdam Zoo. These captivity-born mandrills had never been in contact with drill monkeys, and were unlikely to be hybrids. Their mitochondrial haplotype suggested that they descended from founder animals in Cameroon or northern Gabon, close to the habitat of the drill. SIVdrl has once before been found in a wild-caught mandrill from the same region, indicating that mandrills are naturally infected with a SIVdrl-like virus. This suggests that mandrills are the first primate species to be infected with three strains of SIV: SIVmnd1, SIVmnd2, and SIVdrl.

An Entamoeba sp. strain isolated from rhesus monkey is virulent but genetically different from Entamoeba histolytica.

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Tachibana, Hiroshi; Yanagi, Tetsuo; Pandey, Kishor; Cheng, Xun-Jia; Kobayashi, Seiki; Sherchand, Jeevan B; Kanbara, Hiroji

2007-06-01

An Entamoeba sp. strain, P19-061405, was isolated from a rhesus monkey in Nepal and characterized genetically. The strain was initially identified as Entamoeba histolytica using PCR amplification of peroxiredoxin genes. However, sequence analysis of the 18S rRNA gene showed a 0.8% difference when compared to the reference E. histolytica HM-1:IMSS human strain. Differences were also observed in the 5.8S rRNA gene and the internal transcribed spacer (ITS) regions 1 and 2, and analysis of the serine-rich protein gene from the monkey strain showed unique codon usages compared to E. histolytica isolated from humans. The amino acid sequences of two hexokinases and two glucose phosphate isomerases also differed from those of E. histolytica. Isoenzyme analyses of these enzymes in the monkey strain showed different electrophoretic mobility patterns compared with E. histolytica isolates. Analysis of peroxiredoxin genes indicated the presence of at least seven different types of protein, none of which were identical to proteins in E. histolytica. When the trophozoites from the monkey strain were inoculated into the livers of hamsters, formation of amebic abscesses was observed 7 days after the injection. These results demonstrate that the strain is genetically different from E. histolytica and is virulent. Revival of the name Entamoeba nuttalli is proposed for the organism.

An SIV/macaque model targeted to study HIV-associated neurocognitive disorders.

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Beck, Sarah E; Queen, Suzanne E; Metcalf Pate, Kelly A; Mangus, Lisa M; Abreu, Celina M; Gama, Lucio; Witwer, Kenneth W; Adams, Robert J; Zink, M Christine; Clements, Janice E; Mankowski, Joseph L

2018-04-01

Simian immunodeficiency virus (SIV) infection of pigtailed macaques is a highly representative and well-characterized animal model for HIV neuropathogenesis studies that provides an excellent opportunity to study and develop prognostic markers of HIV-associated neurocognitive disorders (HAND) for HIV-infected individuals. SIV studies can be performed in a controlled setting that enhances reproducibility and offers high-translational value. Similar to observations in HIV-infected patients receiving antiretroviral therapy (ART), ongoing neurodegeneration and inflammation are present in SIV-infected pigtailed macaques treated with suppressive ART. By developing quantitative viral outgrowth assays that measure both CD4+ T cells and macrophages harboring replication competent SIV as well as a highly sensitive mouse-based viral outgrowth assay, we have positioned the SIV/pigtailed macaque model to advance our understanding of latent cellular reservoirs, including potential CNS reservoirs, to promote HIV cure. In addition to contributing to our understanding of the pathogenesis of HAND, the SIV/pigtailed macaque model also provides an excellent opportunity to test innovative approaches to eliminate the latent HIV reservoir in the brain.

Milk composition of captive vervet monkey (Chlorocebus pygerythrus) and rhesus macaque (Macaca mulatta) with observations on gorilla (Gorilla gorilla gorilla) and white handed gibbon (Hylobates lar).

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Osthoff, G; Hugo, A; de Wit, M; Nguyen, T P M; Seier, J

2009-04-01

The nutrient content and fatty acid composition of vervet monkey milk has been determined and is compared with rhesus macaque, and two hominoid apes, the white handed gibbon and gorilla. With 15.7+/-4.1 g protein, 33.1+/-9.4 g fat, and 85.1+/-7.5 g lactose per kg milk, vervet monkey milk does not differ from that of rhesus macaque, and is within the range of other primates. Small amounts (>1 g kg(-1)) of oligosaccharides, glucose, galactose and fucose were noted. In comparison, gorilla milk has a low fat content of 13.8 g kg(-1), but contains high levels of oligosaccharides at 7.0 g kg(-1) milk. The hominoid partner, the white handed gibbon, contains no oligosaccharides and a milk fat content similar to other hominoid species. Differences between vervet monkey and rhesus macaque milks were observed in the electrophoretic pattern of the milk proteins, mainly amongst the kappa- and gamma-caseins, which also differ from that of the hominids. The fatty acid contents of these milks differ from studies where a natural diet of leafy material was available in that a low content of alpha-linolenic acid (18:3n-3) was noted. A phylogenetic effect is observed for the content of 8:0, 10:0 fatty acids between the Cercopithecidae and Hominoidea, and a further phylogenetic effect suggested between the Hylobatidae and Hominidae.

HIV Persistence in Adipose Tissue Reservoirs.

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Couturier, Jacob; Lewis, Dorothy E

2018-02-01

The purpose of this review is to examine the evidence describing adipose tissue as a reservoir for HIV-1 and how this often expansive anatomic compartment contributes to HIV persistence. Memory CD4 T cells and macrophages, the major host cells for HIV, accumulate in adipose tissue during HIV/SIV infection of humans and rhesus macaques. Whereas HIV and SIV proviral DNA is detectable in CD4 T cells of multiple fat depots in virtually all infected humans and monkeys examined, viral RNA is less frequently detected, and infected macrophages may be less prevalent in adipose tissue. However, based on viral outgrowth assays, adipose-resident CD4 T cells are latently infected with virus that is replication-competent and infectious. Additionally, adipocytes interact with CD4 T cells and macrophages to promote immune cell activation and inflammation which may be supportive for HIV persistence. Antiviral effector cells, such as CD8 T cells and NK/NKT cells, are abundant in adipose tissue during HIV/SIV infection and typically exceed CD4 T cells, whereas B cells are largely absent from adipose tissue of humans and monkeys. Additionally, CD8 T cells in adipose tissue of HIV patients are activated and have a late differentiated phenotype, with unique TCR clonotypes of less diversity relative to blood CD8 T cells. With respect to the distribution of antiretroviral drugs in adipose tissue, data is limited, but there may be class-specific penetration of fat depots. The trafficking of infected immune cells within adipose tissues is a common event during HIV/SIV infection of humans and monkeys, but the virus may be mostly transcriptionally dormant. Viral replication may occur less in adipose tissue compared to other major reservoirs, such as lymphoid tissue, but replication competence and infectiousness of adipose latent virus are comparable to other tissues. Due to the ubiquitous nature of adipose tissue, inflammatory interactions among adipocytes and CD4 T cells and macrophages, and

Effects of testosterone on attention and memory for emotional stimuli in male rhesus monkeys.

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King, Hanna M; Kurdziel, Laura B; Meyer, Jerrold S; Lacreuse, Agnès

2012-03-01

Increasing evidence in humans and other animals suggests that testosterone (T) plays an important role in modulating emotion. We previously reported that T treatment in rhesus monkeys undergoing chemically induced hypogonadism results in increased watching time of videos depicting fights between unfamiliar conspecifics (Lacreuse et al., 2010). In the current study, we aimed to further investigate the effect of T manipulations on attention and memory for emotional stimuli in male rhesus monkeys. Six males (7 years old) were administered Depot Lupron to suppress endogenous T levels and treated with either testosterone enanthate (TE, 5 mg/kg) or oil, before crossing over to the alternate treatment. Animals were tested for 16 weeks on two computerized touchscreen tasks with both social and nonsocial emotional and neutral stimuli. The Dot-Probe task was used to measure attention, and the Delayed-Non-Matching-to-Sample task with a 1s delay (DNMS) was used to measure recognition memory for these stimuli. Performance on the two tasks was examined during each of four month-long phases: Baseline, Lupron alone, Lupron+TE and Lupron+oil. It was predicted that T administration would lead to increased attention to negative social stimuli (i.e., negative facial expressions of unfamiliar conspecifics) and would improve memory for such stimuli. We found no evidence to support these predictions. In the Dot-Probe task, an attentional bias towards negative social stimuli was observed at baseline, but T treatment did not enhance this bias. Instead, monkeys had faster response times when treated with T compared to oil, independently of the emotional valence or social relevance of stimuli, perhaps reflecting an enhancing effect of T on reward sensitivity or general arousal. In the DNMS, animals had better memory for nonsocial compared to social stimuli and showed the poorest performance in the recognition of positive facial expressions. However, T did not affect performance on the task

Anti-α4 Antibody Treatment Blocks Virus Traffic to the Brain and Gut Early, and Stabilizes CNS Injury Late in Infection

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Campbell, Jennifer H.; Ratai, Eva-Maria; Autissier, Patrick; Nolan, David J.; Tse, Samantha; Miller, Andrew D.; González, R. Gilberto; Salemi, Marco; Burdo, Tricia H.; Williams, Kenneth C.

2014-01-01

Four SIV-infected monkeys with high plasma virus and CNS injury were treated with an anti-α4 blocking antibody (natalizumab) once a week for three weeks beginning on 28 days post-infection (late). Infection in the brain and gut were quantified, and neuronal injury in the CNS was assessed by MR spectroscopy, and compared to controls with AIDS and SIV encephalitis. Treatment resulted in stabilization of ongoing neuronal injury (NAA/Cr by 1H MRS), and decreased numbers of monocytes/macrophages a...

Occurrence of specific influenza antibodies in saliva and nasal secretion of monkeys (Macacus rhesus) after oral administration of influenza vaccine inactivated by gamma rays

International Nuclear Information System (INIS)

Tischner, H.; Huyuh, P.L.; Phan, P.N.; Bergmann, K.C.; Hoang, T.N.; Luther, P.; Nordheim, W.; Braeuniger, S.; Waldman, R.H.

1984-01-01

Antibodies in nasal secretion and saliva were measured in 10 Macacus rhesus wich had been immunized orally with a 60 Co-gamma-inactivated influenza vaccine. Prior to immunization monkeys had no detectable antibodies against hemagglutinin (HA) and neuraminidase, resp. in sera or secretions. Oral immunization using intraoesophageal tubing, induced the occurrence of both antiobodies in pilocarpine-stimulated secretions within 28 days but not in sera. 6 monkeys reacted with increasing HA antibodies in nasal secretions and 10 monkeys with increasing neuraminidase antibodies. Salivary HA antibodies occurred in 8 of 10 and neuraminidase antibodies in 9 of 10 animals. In most cases antibodies occurred in both secretions simultaneously. These results demonstrate the stimulation of antibodies specific to influenza in the respiratory tract of monkeys after oral immunization with an inactivated vaccine, for the first time. (author)

Crossmodal integration of conspecific vocalizations in rhesus macaques.

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Christa Payne

Full Text Available Crossmodal integration of audio/visual information is vital for recognition, interpretation and appropriate reaction to social signals. Here we examined how rhesus macaques process bimodal species-specific vocalizations by eye tracking, using an unconstrained preferential looking paradigm. Six adult rhesus monkeys (3M, 3F were presented two side-by-side videos of unknown male conspecifics emitting different vocalizations, accompanied by the audio signal corresponding to one of the videos. The percentage of time animals looked to each video was used to assess crossmodal integration ability and the percentages of time spent looking at each of the six a priori ROIs (eyes, mouth, and rest of each video were used to characterize scanning patterns. Animals looked more to the congruent video, confirming reports that rhesus monkeys spontaneously integrate conspecific vocalizations. Scanning patterns showed that monkeys preferentially attended to the eyes and mouth of the stimuli, with subtle differences between males and females such that females showed a tendency to differentiate the eye and mouth regions more than males. These results were similar to studies in humans indicating that when asked to assess emotion-related aspects of visual speech, people preferentially attend to the eyes. Thus, the tendency for female monkeys to show a greater differentiation between the eye and mouth regions than males may indicate that female monkeys were slightly more sensitive to the socio-emotional content of complex signals than male monkeys. The current results emphasize the importance of considering both the sex of the observer and individual variability in passive viewing behavior in nonhuman primate research.

Concurrent determination of bisphenol A pharmacokinetics in maternal and fetal rhesus monkeys

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Patterson, Tucker A. [Division of Neurotoxicology, National Center for Toxicological Research, Jefferson, AR 72079 (United States); Twaddle, Nathan C. [Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, AR 72079 (United States); Roegge, Cindy S. [Division of Neurotoxicology, National Center for Toxicological Research, Jefferson, AR 72079 (United States); Callicott, Ralph J. [U.S. Food and Drug Administration and Priority One Services Corp, Jefferson, AR 72079 (United States); Fisher, Jeffrey W. [Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, AR 72079 (United States); Doerge, Daniel R., E-mail: daniel.doerge@fda.hhs.gov [Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, AR 72079 (United States)

2013-02-15

Bisphenol A (BPA) is an important industrial chemical used as the monomer for polycarbonate plastic and in epoxy resins for food can liners. Worldwide biomonitoring studies consistently find a high prevalence of BPA conjugates in urine (> 90%) in amounts consistent with aggregate exposure at levels below 1 μg/kg bw/d. The current study used LC/MS/MS to measure concurrently the pharmacokinetics of aglycone (active) and conjugated (inactive) deuterated BPA (d6) in maternal and fetal rhesus monkey serum, amniotic fluid, and placenta following intravenous injection in the dam (100 μg/kg bw). Internal exposures of the fetus to aglycone d6-BPA (serum AUC) were attenuated by maternal, placental, and fetal Phase II metabolism to less than half that in the dam. Levels of aglycone and conjugated d6-BPA measured in whole placenta were consistent with a role in metabolic detoxification. The monotonic elimination of aglycone d6-BPA from the fetal compartment accompanied by persistent conjugate levels provides further evidence arguing against the hypothesis that BPA conjugates are selectively deconjugated by either the placenta or fetus. These results also provide benchmarks to guide the interpretation of human cord blood, amniotic fluid, and placenta sampling and measurement strategies as a basis for estimating fetal exposures to BPA. This study in a non-human primate model provides additional pharmacokinetic data for use in PBPK modeling of perinatal exposures to BPA from food contact, medical devices, and other environmental sources. - Highlights: ► Maternal, placental, and fetal Phase II metabolism attenuate fetal exposure to BPA. ► Serum AUC for aglycone BPA in fetal monkeys is less than half of that in the dam. ► BPA profiles in monkey fetus rule out selective deconjugation and accumulation. ► BPA levels in monkey placenta are similar to other metabolically active tissues. ► Some published human cord blood data for BPA are inconsistent with these measurements.

Low Lactobacilli abundance and polymicrobial diversity in the lower reproductive tract of female rhesus monkeys do not compromise their reproductive success.

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Amaral, Wellington Z; Lubach, Gabriele R; Kapoor, Amita; Proctor, Alexandra; Phillips, Gregory J; Lyte, Mark; Coe, Christopher L

2017-10-01

The lower reproductive tract of nonhuman primates is colonized with a diverse microbiota, resembling bacterial vaginosis (BV), a gynecological condition associated with negative reproductive outcomes in women. Our 4 aims were to: (i) assess the prevalence of low Lactobacilli and a BV-like profile in female rhesus monkeys; (ii) quantify cytokines in their cervicovaginal fluid (CVF); (iii) examine the composition and structure of their mucosal microbiota with culture-independent sequencing methods; and (iv) evaluate the potential influence on reproductive success. CVF specimens were obtained from 27 female rhesus monkeys for Gram's staining, and to determine acidity (pH), and quantify proinflammatory cytokines. Based on Nugent's classification, 40% had a score of 7 or higher, which would be indicative of BV in women. Nugent scores were significantly correlated with the pH of the CVF. Interleukin-1ß was present at high concentrations, but not further elevated by high Nugent scores. Vaginal swabs were obtained from eight additional females to determine microbial diversity by rRNA gene amplicon sequencing. At the phylum level, the Firmicutes/Bacteroidetes ratio was low. The relative abundance of Lactobacilli was also low (between 3% and 17%), and 11 other genera were present at >1%. However, neither the microbial diversity in the community structure, nor high Nugent scores, was associated with reduced fecundity. Female monkeys provide an opportunity to understand how reproductive success can be sustained in the presence of a diverse polymicrobial community in the reproductive tract. © 2017 Wiley Periodicals, Inc.

Changes in food intake and abnormal behavior using a puzzle feeder in newly acquired sub-adult rhesus monkeys (Macaca mulatta): a short term study.

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Lee, Jae-Il; Lee, Chi-Woo; Kwon, Hyouk-Sang; Kim, Young-Tae; Park, Chung-Gyu; Kim, Sang-Joon; Kang, Byeong-Cheol

2008-10-01

The majority of newly acquired nonhuman primates encounter serious problems adapting themselves to new environments or facilities. In particular, loss of appetite and abnormal behavior can occur in response to environmental stresses. These adaptation abnormalities can ultimately have an affect on the animal's growth and well-being. In this study, we evaluated the affects of a puzzle feeder on the food intake and abnormal behavior of newly acquired rhesus monkeys for a short period. The puzzle feeder was applied to 47- to 58-month-old animals that had never previously encountered one. We found that there was no difference in the change of food intake between the bucket condition and the puzzle feeder condition. In contrast, the time spent for consumption of food was three times longer in the puzzle feeder condition than in the bucket condition. Two monkeys initially exhibited stereotypic behavior. One showed a decreasing, and the other an increasing pattern of abnormal behavior after introduction of the puzzle feeder. In conclusion, this result suggests that over a short period, the puzzle feeder can only affect the time for food consumption since it failed to affect the food intake and did not consistently influence stereotypic behaviors in newly acquired rhesus monkeys.

Evolutionary and biomedical insights from the rhesus macaque genome

DEFF Research Database (Denmark)

Gibbs, Richard A; Rogers, Jeffrey; Katze, Michael G

2007-01-01

The rhesus macaque (Macaca mulatta) is an abundant primate species that diverged from the ancestors of Homo sapiens about 25 million years ago. Because they are genetically and physiologically similar to humans, rhesus monkeys are the most widely used nonhuman primate in basic and applied...

Targeting α4β7 integrin reduces mucosal transmission of simian immunodeficiency virus and protects gut-associated lymphoid tissue from infection.

Science.gov (United States)

Byrareddy, Siddappa N; Kallam, Brianne; Arthos, James; Cicala, Claudia; Nawaz, Fatima; Hiatt, Joseph; Kersh, Ellen N; McNicholl, Janet M; Hanson, Debra; Reimann, Keith A; Brameier, Markus; Walter, Lutz; Rogers, Kenneth; Mayne, Ann E; Dunbar, Paul; Villinger, Tara; Little, Dawn; Parslow, Tristram G; Santangelo, Philip J; Villinger, Francois; Fauci, Anthony S; Ansari, Aftab A

2014-12-01

α4β7 integrin-expressing CD4(+) T cells preferentially traffic to gut-associated lymphoid tissue (GALT) and have a key role in HIV and simian immunodeficiency virus (SIV) pathogenesis. We show here that the administration of an anti-α4β7 monoclonal antibody just prior to and during acute infection protects rhesus macaques from transmission following repeated low-dose intravaginal challenges with SIVmac251. In treated animals that became infected, the GALT was significantly protected from infection and CD4(+) T cell numbers were maintained in both the blood and the GALT. Thus, targeting α4β7 reduces mucosal transmission of SIV in macaques.

Discriminative stimulus properties of intragastrically administered d-amphetamine and pentobarbital in rhesus monkeys.

Science.gov (United States)

de la Garza, R; Johanson, C E

1987-12-01

Rhesus monkeys were trained to discriminate intragastrically administered d-amphetamine (AMPH) or pentobarbital (PENTO) from saline using a signaled shock-avoidance trail procedure. All monkeys maintained criterion levels (greater than 90% drug-appropriate responding) throughout the duration of the study during training sessions. In the AMPH experiment, the anorectics diethylpropion, mazindol, phendimetrazine, phenmetrazine and phentermine completely substituted for the training dose of AMPH. The atypical antidepressant bupropion and the psychomotor stimulant methylphenidate also completely substituted for AMPH. Other anorectics including benzphetamine, clortermine, fenetylline, mefenorex and the psychomotor stimulant pemoline that share some pharmacological properties with AMPH substituted for AMPH in some, but not all, of the monkeys tested. The anorectics fenfluramine and chlorphentermine failed to substitute for AMPH. Drugs from other pharmacological classes such as morphine, diazepam, nortripyline and PENTO also failed to substitute for AMPH, indicating pharmacological specificity. In the PENTO experiment, the benzodiazepines alprazolam, bromazepam, diazepam, flurazepam, halazepam, lorazepam, midazolam, oxazepam, temazepam and triazolam and the sedatives methaqualone and phenobarbital completely substituted for the training dose of PENTO. The nonbenzodiazepine anxiolytic CL 218,872 only partially substituted for PENTO. In addition, morphine and AMPH failed to substitute for PENTO, indicating pharmacological specificity. In summary, drugs delivered intragastrically functioned as discriminative stimuli in a drug-class specific manner. The ability to use drugs delivered by this route as discriminative stimuli provides a way to compare anorectic drugs to AMPH or sedative drugs to PENTO under conditions that resemble the mode of human consumption to determine whether these drugs are likely to be associated with AMPH-like or PENTO-like drug dependence.

Metabolic fate of the beta-blocker 14C-bupranolol in humans, dogs, and rhesus monkeys

International Nuclear Information System (INIS)

Waller, A.R.; Chasseaud, L.F.; Bonn, R.; Taylor, T.; Darragh, A.; Girkin, R.; Down, W.H.; Doyle, E.

1982-01-01

An oral dose of 14 C-bupranolol hydrochloride was well absorbed by humans (100 mg), dogs (1 mg/kg), and rhesus monkeys (1 mg/kg). These species excreted 87.8 and 3.5%, 81.1 and 13.6%, and 92.9 ad 5.0% of the 14 C-dose in urine and feces, respectively, mainly in 12 or 24 hr. Mean plasma levels of 14 C, which appeared to be almost entirely associated with a single metabolite, peaked at 1 hr in humans (1.6 micrograms-equiv./ml) and dogs (1.6 micrograms-/ml) and at 2 hr in monkeys (0.8 micrograms-equiv./ml). Concentrations initially declined with similar half-lives (about 1.5 hr) in all three species. Biliary excretion of 14 C occurred in the animal species in which also peak plasma 14 C levels exceeded those in most tissues. Unchanged bupranolol was not detected in plasma; the peak plasma and urinary 14 C was mainly associated (greater than 90% in humans) with a metabolite produced by oxidation of the aromatic ring methyl group of bupranolol to a carboxyl group

Response of sublethally irradiated monkeys to a replicating viral antigen

International Nuclear Information System (INIS)

Hilmas, D.E.; Spertzel, R.O.

1975-01-01

Temporal effects of exposure to sublethal, total-body x radiation (400 R) on responses to vaccination with the attenuated Venezuelan equine encephalomyelitis vaccine virus, TC-83, were examined in rhesus monkeys. Viremia, often with delayed onset, was prolonged even when irradiation preceded vaccination by 28 days. Virus titers were increased, particularly in groups irradiated 4 or 7 days before vaccination. Delay in appearance of hemagglutination-inhibition and serum-neutralizing antibody correlated closely with persistence of viremia in irradiated-vaccinated monkeys. The temporal course of antibody response was markedly affected by the interval between irradiation and injection of this replicating antigen. With longer intervals between irradiation and vaccination, the somewhat depressed antibody responses approached normal or surpassed those of nonirradiated monkeys. Vaccination 14 days after radiation exposure resulted in lethality to 8 of 12 monkeys, apparently as a result of secondary infection. The additional lymphopenic stress due to the effect of TC-83, superimposed on the severely depressed hematopoietic competence at 14 days, undoubtedly contributed to this increased susceptibility to latent infection

Age-Specific Gene Expression Profiles of Rhesus Monkey Ovaries Detected by Microarray Analysis

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Hengxi Wei

2015-01-01

Full Text Available The biological function of human ovaries declines with age. To identify the potential molecular changes in ovarian aging, we performed genome-wide gene expression analysis by microarray of ovaries from young, middle-aged, and old rhesus monkeys. Microarray data was validated by quantitative real-time PCR. Results showed that a total of 503 (60 upregulated, 443 downregulated and 84 (downregulated genes were differentially expressed in old ovaries compared to young and middle-aged groups, respectively. No difference in gene expression was found between middle-aged and young groups. Differentially expressed genes were mainly enriched in cell and organelle, cellular and physiological process, binding, and catalytic activity. These genes were primarily associated with KEGG pathways of cell cycle, DNA replication and repair, oocyte meiosis and maturation, MAPK, TGF-beta, and p53 signaling pathway. Genes upregulated were involved in aging, defense response, oxidation reduction, and negative regulation of cellular process; genes downregulated have functions in reproduction, cell cycle, DNA and RNA process, macromolecular complex assembly, and positive regulation of macromolecule metabolic process. These findings show that monkey ovary undergoes substantial change in global transcription with age. Gene expression profiles are useful in understanding the mechanisms underlying ovarian aging and age-associated infertility in primates.

Decreased number of CD4+ and CD8+ T cells that express the interleukin-7 receptor in blood and tissues of SIV-infected macaques

International Nuclear Information System (INIS)

Moniuszko, Marcin; Edghill-Smith, Yvette; Venzon, David; Stevceva, Liljana; Nacsa, Janos; Tryniszewska, Elzbieta; Tsai, Wen-Po; Franchini, Genoveffa

2006-01-01

Acute HIV/SIV (human/simian immunodeficiency virus) infection results in severe CD4 + T cell depletion in lymphoid compartments. During the chronic phase of infection, CD4 + T cell numbers rebound in blood but remain low in the gut-associated lymphoid tissue (GALT), even when viral replication is suppressed by antiretroviral therapy (ART). Thus, strategies to repopulate lymphoid compartments may ameliorate the clinical outcome of HIV/SIV infection. Interleukin (IL)-7 is a key cytokine for the maintenance of homeostatic proliferation of T cells. In HIV/SIV infection, IL-7 expression is increased, likely to compensate for T cell loss, suggesting that supraphysiological administration of IL-7 could provide additional benefit. However, the ability of T cells to respond to IL-7 is dependent on the level of expression of the IL-7 receptor (IL-7R) in T cells in various body compartments. In here, we investigated the proportion of IL-7R + T cells in blood, spleen, gut, and genitourinary tract of healthy and SIV-infected macaques with various degrees of CD4 + T cell depletion. We found that the percentage of T cells expressing IL-7R was significantly lower in both CD4 + and CD8 + T cell subsets in SIV-infected macaques than in healthy animals and this decrease directly correlated with the CD4 + T cell number. Importantly, the proportion of CD4 + and CD8 + T cells expressing IL-7R in blood paralleled that found in tissues. IL-7R + T cells within the SIV-specific CD8 + T cells varied and were lowest in most tissues of viremic macaques, likely reflecting continuous antigen stimulation of effector cells

Topographic and age-related changes of the retinal epithelium and Bruch's membrane of rhesus monkeys.

Science.gov (United States)

Gouras, Peter; Ivert, Lena; Neuringer, Martha; Mattison, Julie A

2010-07-01

To examine structural differences in the retinal pigmented epithelium (RPE) and Bruch's membrane of rhesus monkeys (Macaca mulatta) as a function of topography and age. The retinas of two old (24 and 26 years old) and two young (1 and 6 years old) female monkeys were examined by light fluorescence and electron microscopy at the macula, equator, and ora serrata. All monkeys lacked fluorescence and lipofuscin granules in the RPE at the ora serrata where photoreceptors are absent. The equator and macula showed intense fluorescence and many lipofuscin granules in the RPE of the old but not the young monkeys. At the ora, the RPE contained many dense round melanin granules throughout the cell. At the equator and macula, melanin granules were more apical, less frequent, and often elongated. Mitochondria were clustered at the basal side of the RPE cell near infolds of the plasma membrane. Both mitochondria and infolds tended to increase toward the macula. In all regions, the basal lamina of the RPE did not penetrate the extracellular space adjacent to infolds. The elastin layer of Bruch's membrane was wide at the ora and equator and thinner at the macula. In the old monkeys, drusen were found at all retinal regions between the basal lamina and the internal collagen layer of Bruch's membrane. The drusen were often membrane-bound with a basal lamina and contained material resembling structures in the RPE. Lack of fluorescence and lipofuscin in the RPE at the ora serrata, where photoreceptors are absent, confirms that RPE fluorescence occurs only where outer segments are phagocytized. Mitochondrial clustering indicates that the basal side of the RPE cell uses the most energy and this becomes maximal at the macula. The presence of age-related degenerative changes and drusen at all retinal locations in the older monkeys, even at the ora where RPE lipofuscin was absent, indicates that these processes are not dependent on local lipofuscin accumulation. Therefore lipofuscin

Dermal absorption of the insecticide lindane (1 delta, 2 delta, 3 beta, 4 delta, 5 delta, 6 beta-hexachlorocyclohexane) in rats and rhesus monkeys: Effect of anatomical site

International Nuclear Information System (INIS)

Moody, R.P.; Ritter, L.

1989-01-01

Dermal absorption of the insecticide lindane (1 delta, 2 delta, 3 beta, 4 delta, 5 delta, 6 beta-hexachlorocyclohexane) was determined in rats and rhesus monkeys. Lindane is in widespread use as a 1% cream or lotion scabicide formulation and as a 1% miticide shampoo for body lice control in humans. Results obtained following our in vivo dermal absorption procedure demonstrated that 18 +/- 4.1%, 34 +/- 5.2%, and 54 +/- 26.3% of the applied dose was absorbed following topical applications at a rate of 1.5 micrograms/cm2 (6.2 micrograms/100 microliters of acetone) of the 14C-labeled pesticide to 4.2-cm2 regions of the forearm (n = 8), forehead (n = 7), and palm (n = 4) of rhesus monkeys, respectively. Dose sites were washed with soapy water 24 h posttreatment. Comparative studies in rats (n = 5) dosed middorsally demonstrated 31 +/- 9.5% absorption. Statistical analysis of the 14C excretion kinetics demonstrated slower clearance of lindane from rats than monkey forearm, forehead, or palm. Intramuscular (im) injections of 14C-lindane gave 52 +/- 7.1% recovery in monkey (n = 8) and 64 +/- 5.9% in rats (n = 5), suggesting body storage of this lipophilic chemical

Pre-treatment with Toll-like receptor 4 antagonist inhibits lipopolysaccharide-induced preterm uterine contractility, cytokines, and prostaglandins in rhesus monkeys

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Adams Waldorf, Kristina M.; Persing, David; Novy, Miles J.; Sadowsky, Drew W.; Gravett, Michael G.

2009-01-01

Intra-uterine infection, which occurs in the majority of early preterm births, triggers an immune response culminating in preterm labor. We hypothesized that blockade of lipopolysaccharide (LPS)-induced immune responses by a Toll-like receptor 4 antagonist (TLR4A) would prevent elevations in amniotic fluid (AF) cytokines, prostaglandins, and uterine contractility. Chronically catheterized rhesus monkeys at 128-147 days gestation received intra-amniotic infusions of either: 1) saline (n=6), 2) LPS (0.15-10μg; n=4), or 3) TLR4A pre-treatment with LPS (10 μg) one hour later (n=4). AF cytokines, prostaglandins, and uterine contractility were compared using oneway ANOVA with Bonferroni-adjusted pairwise comparisons. Compared to saline controls, LPS induced significant elevations in AF IL-8, TNF-α, PGE2, PGF2α, and uterine contractility (p<0.05). In contrast, TLR4A pre-treatment inhibited LPS-induced uterine activity and was associated with significantly lower AF IL-8, TNF-α, PGE2, and PGF2α versus LPS alone (p<0.05). Toll-like receptor antagonists, together with antibiotics, may delay or prevent infection-associated preterm birth. PMID:18187405

Serotonin transporter genotype modulates social reward and punishment in rhesus macaques.

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Karli K Watson

Full Text Available Serotonin signaling influences social behavior in both human and nonhuman primates. In humans, variation upstream of the promoter region of the serotonin transporter gene (5-HTTLPR has recently been shown to influence both behavioral measures of social anxiety and amygdala response to social threats. Here we show that length polymorphisms in 5-HTTLPR predict social reward and punishment in rhesus macaques, a species in which 5-HTTLPR variation is analogous to that of humans.In contrast to monkeys with two copies of the long allele (L/L, monkeys with one copy of the short allele of this gene (S/L spent less time gazing at face than non-face images, less time looking in the eye region of faces, and had larger pupil diameters when gazing at photos of a high versus low status male macaques. Moreover, in a novel primed gambling task, presentation of photos of high status male macaques promoted risk-aversion in S/L monkeys but promoted risk-seeking in L/L monkeys. Finally, as measured by a "pay-per-view" task, S/L monkeys required juice payment to view photos of high status males, whereas L/L monkeys sacrificed fluid to see the same photos.These data indicate that genetic variation in serotonin function contributes to social reward and punishment in rhesus macaques, and thus shapes social behavior in humans and rhesus macaques alike.

Mechanisms of CD8+ T cell-mediated suppression of HIV/SIV replication.

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McBrien, Julia Bergild; Kumar, Nitasha A; Silvestri, Guido

2018-02-10

In this article, we summarize the role of CD8 + T cells during natural and antiretroviral therapy (ART)-treated HIV and SIV infections, discuss the mechanisms responsible for their suppressive activity, and review the rationale for CD8 + T cell-based HIV cure strategies. Evidence suggests that CD8 + T cells are involved in the control of virus replication during HIV and SIV infections. During early HIV infection, the cytolytic activity of CD8 + T cells is responsible for control of viremia. However, it has been proposed that CD8 + T cells also use non-cytolytic mechanisms to control SIV infection. More recently, CD8 + T cells were shown to be required to fully suppress virus production in ART-treated SIV-infected macaques, suggesting that CD8 + T cells are involved in the control of virus transcription in latently infected cells that persist under ART. A better understanding of the complex antiviral activities of CD8 + T cells during HIV/SIV infection will pave the way for immune interventions aimed at harnessing these functions to target the HIV reservoir. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Experimentally induced gestational androgen excess disrupts glucoregulation in rhesus monkey dams and their female offspring.

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Abbott, David H; Bruns, Cristin R; Barnett, Deborah K; Dunaif, Andrea; Goodfriend, Theodore L; Dumesic, Daniel A; Tarantal, Alice F

2010-11-01

Discrete fetal androgen excess during early gestation in rhesus monkeys (Macaca mulatta) promotes endocrine antecedents of adult polycystic ovary syndrome (PCOS)-like traits in female offspring. Because developmental changes promoting such PCOS-like metabolic dysfunction remain unclear, the present study examined time-mated, gravid rhesus monkeys with female fetuses, of which nine gravid females received 15 mg of testosterone propionate (TP) subcutaneously daily from 40 to 80 days (first to second trimesters) of gestation [term, mean (range): 165 (155-175) days], whereas an additional six such females received oil vehicle injections over the same time interval. During gestation, ultrasonography quantified fetal growth measures and was used as an adjunct for fetal blood collections. At term, all fetuses were delivered by cesarean section for postnatal studies. Blood samples were collected from dams and infants for glucose, insulin, and total free fatty acid (FFA) determinations. TP injections transiently accelerated maternal weight gain in dams, very modestly increased head diameter of prenatally androgenized (PA) fetuses, and modestly increased weight gain in infancy compared with concurrent controls. Mild to moderate glucose intolerance, with increased area-under-the-curve circulating insulin values, occurred in TP-injected dams during an intravenous glucose tolerance test in the early second trimester. Moreover, reduced circulating FFA levels occurred in PA fetuses during a third trimester intravenous glucagon-tolbutamide challenge (140 days gestation), whereas excessive insulin sensitivity and increased insulin secretion relative to insulin sensitivity occurred in PA infants during an intravenous glucose-tolbutamide test at ∼1.5 mo postnatal age. Data from these studies suggest that experimentally induced fetal androgen excess may result in transient hyperglycemic episodes in the intrauterine environment that are sufficient to induce relative increases in

Effects of 12 days exposure to simulated microgravity on central circulatory hemodynamics in the rhesus monkey

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Convertino, V. A.; Koenig, S. C.; Krotov, V. P.; Fanton, J. W.; Korolkov, V. I.; Trambovetsky, E. V.; Ewert, D. L.; Truzhennikov, A.; Latham, R. D.

1998-01-01

Central circulatory hemodynamic responses were measured before and during the initial 9 days of a 12-day 10 degrees head-down tilt (HDT) in 4 flight-sized juvenile rhesus monkeys who were surgically instrumented with a variety of intrathoracic catheters and blood flow sensors to assess the effects of simulated microgravity on central circulatory hemodynamics. Each subject underwent measurements of aortic and left ventricular pressures, and aortic flow before and during HDT as well as during a passive head-up postural test before and after HDT. Heart rate, stroke volume, cardiac output, and left ventricular end-diastolic pressure were measured, and dP/dt and left ventricular elastance was calculated from hemodynamic measurements. The postural test consisted of 5 min of supine baseline control followed by 5 minutes of 90 degrees upright tilt (HUT). Heart rate, stroke volume, cardiac output, and left ventricular end-diastolic pressure showed no consistent alterations during HDT. Left ventricular elastance was reduced in all animals throughout HDT, indicating that cardiac compliance was increased. HDT did not consistently alter left ventricular +dP/dt, indicating no change in cardiac contractility. Heart rate during the post-HDT HUT postural test was elevated compared to pre-HDT while post-HDT cardiac output was decreased by 52% as a result of a 54% reduction in stroke volume throughout HUT. Results from this study using an instrumented rhesus monkey suggest that exposure to microgravity may increase ventricular compliance without alternating cardiac contractility. Our project supported the notion that an invasively-instrumented animal model should be viable for use in spaceflight cardiovascular experiments to assess potential changes in myocardial function and cardiac compliance.

Effects of continuous nicotine treatment and subsequent termination on cocaine versus food choice in male rhesus monkeys.

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Schwienteck, Kathryn L; Negus, S Stevens; Poklis, Justin L; Banks, Matthew L

2015-10-01

One complicating factor in cocaine addiction may be concurrent exposure and potential dependence on nicotine. The aim of the present study was to determine the effects of continuous nicotine treatment and subsequent termination on cocaine versus food choice in rhesus monkeys (Macaca mulatta). For comparison, we also determined effects of the nicotinic receptor antagonist mecamylamine on cocaine versus food choice during continuous saline and nicotine treatment. Rhesus monkeys (N = 3) responded under a concurrent schedule of food pellet (1 g) and intravenous cocaine (0-0.1 mg/kg/injection) availability. Saline and ascending nicotine doses (0.1-1.0 mg/kg/hr, intravenous) were continuously infused for 7-day treatment periods and separated by 24-hr saline treatment periods. Acute effects of mecamylamine (0.32-1.8 mg/kg, intramuscular, 15 min pretreatment) were determined during continuous saline and 0.32-mg/kg/hr nicotine treatments. During saline treatment, cocaine maintained a dose-dependent increase in cocaine choice. Nicotine treatment did not alter cocaine versus food choice. In contrast, preference of 0.032 mg/kg/injection cocaine was attenuated 24 hr following termination of 0.32-mg/kg/hr nicotine treatment, despite no somatic abstinence signs being observed. Acute mecamylamine enhanced cocaine choice during saline treatment and mainly suppressed rates of behavior during nicotine treatment. Overall, continuous nicotine exposure, up to 1 mg/kg/hr, does not enhance cocaine choice and does not produce nicotine dependence, as demonstrated by the lack of abstinence signs. (c) 2015 APA, all rights reserved).

[18F]Fluoroazabenzoxazoles as potential amyloid plaque PET tracers: synthesis and in vivo evaluation in rhesus monkey

International Nuclear Information System (INIS)

Hostetler, Eric D.; Sanabria-Bohórquez, Sandra; Fan Hong; Zeng, Zhizhen; Gammage, Linda; Miller, Patricia; O'Malley, Stacey; Connolly, Brett; Mulhearn, James; Harrison, Scott T.; Wolkenberg, Scott E.; Barrow, James C.; Williams, David L.; Hargreaves, Richard J.; Sur, Cyrille; Cook, Jacquelynn J.

2011-01-01

Introduction: An 18 F-labeled positron emission tomography (PET) tracer for amyloid plaque is desirable for early diagnosis of Alzheimer's disease, particularly to enable preventative treatment once effective therapeutics are available. Similarly, such a tracer would be useful as a biomarker for enrollment of patients in clinical trials for evaluation of antiamyloid therapeutics. Furthermore, changes in the level of plaque burden as quantified by an amyloid plaque PET tracer may provide valuable insights into the effectiveness of amyloid-targeted therapeutics. This work describes our approach to evaluate and select a candidate PET tracer for in vivo quantification of human amyloid plaque. Methods: Ligands were evaluated for their in vitro binding to human amyloid plaques, lipophilicity and predicted blood–brain barrier permeability. Candidates with favorable in vitro properties were radiolabeled with 18 F and evaluated in vivo. Baseline PET scans in rhesus monkey were conducted to evaluate the regional distribution and kinetics of each tracer using tracer kinetic modeling methods. High binding potential in cerebral white matter and cortical grey matter was considered an unfavorable feature of the candidate tracers. Results: [ 18 F]MK-3328 showed the most favorable combination of low in vivo binding potential in white matter and cortical grey matter in rhesus monkeys, low lipophilicity (Log D=2.91) and high affinity for human amyloid plaques (IC 50 =10.5±1.3 nM). Conclusions: [ 18 F]MK-3328 was identified as a promising PET tracer for in vivo quantification of amyloid plaques, and further evaluation in humans is warranted.

A novel CD4-conjugated ultraviolet light-activated photocatalyst inactivates HIV-1 and SIV efficiently.

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Yamaguchi, Koushi; Sugiyama, Takahiro; Kato, Shinji; Kondo, Yoichi; Ageyama, Naohide; Kanekiyo, Masaru; Iwata, Misao; Koyanagi, Yoshio; Yamamoto, Naoki; Honda, Mitsuo

2008-08-01

In this study, we found that the electric potential derived from the redox reaction of ultraviolet (UV)-illuminated CD4-conjugated titanium dioxide (TiO2) inactivated a wide range of high-titered primary HIV-1 isolates, regardless of virus co-receptor usage or genetic clade. In vitro incubation of HIV-1 isolates with CD4-conjugated TiO2 (CD4-TiO2) followed by UV illumination led to inhibition of viral infectivity in both H9 cells and peripheral blood mononuclear cells as well as to the complete inactivation of plasma virions from HIV-1-infected individuals. Treatment with a newly established extra-corporeal circulation system with the photocatalyst in rhesus macaques completely inactivated plasma virus in the system and effectively reduced the infectious plasma viral load. Furthermore, plasma viremia and infectious viral loads were controlled following a second therapeutic photocatalyst treatment during primary SIV(mac239) infection of macaques. Our findings suggest that this therapeutic immunophysical strategy may help control human immunodeficiency viral infection in vivo.

An alert of Mycobacterium tuberculosis infection of rhesus macaques in a wild zoo in China.

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Gong, Wenping; Yang, Yourong; Luo, Yi; Li, Ning; Bai, Xuejuan; Liu, Yinping; Zhang, Junxian; Chen, Ming; Zhang, Chenglin; Wu, Xueqiong

2017-10-30

Mycobacterium tuberculosis, the pathogen that causes tuberculosis (TB), is becoming increasingly recognized as an important cause of fatal chronic illnesses in China. In this study, we report an infectious disease among 84 rhesus macaques at a Chinese zoo. Their clinical signs and symptoms were very similar with the manifestations of TB in humans. To determine the potential pathogens of this outbreak, many methods were used. First, tuberculin skin tests showed that none of the monkeys displayed significant skin reactions. Subsequently, the sera were tested for specific antibody IgG; 29 (34.5%) and 39 (46.4%) blood samples tested positive by TB-IgG and TB-DOT, respectively. Radiographic examination showed characteristic imageology changes in 14 (16.7%) monkeys. One individual determined as positive by the above three methods was euthanized, and histopathological analysis demonstrated typical granulomas and caseous necrosis in the lung, liver, spleen, and intestine. Furthermore, the pathogenic mycobacteria were isolated from lung lobe, cultured on acidic Lowenstein-Jensen culture medium, and identified as M. tuberculosis by real-time PCR and DNA sequencing. Nevertheless, the origin of the infection remained unknown. These findings emphasize the need to strengthen the management and training of staff, especially those working at animal shelters.

Adipose Tissue: Sanctuary for HIV/SIV Persistence and Replication.

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Pallikkuth, Suresh; Mohan, Mahesh

2015-12-01

This commentary highlights new findings from a recent study identifying adipose tissue as a potential HIV reservoir and a major site of inflammation during chronic human/simian immunodeficiency virus (HIV/SIV) infection. A concise discussion about upcoming challenges and new research avenues for reducing chronic adipose inflammation during HIV/SIV infection is presented. Copyright © 2015 Elsevier Ltd. All rights reserved.

The Effect of Extremely Low Frequency Electromagnetic Fields on Visual Learning & Memory and Anatomical Structures of the Brain in Male Rhesus Monkeys

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Elahe Tekieh

2018-04-01

Full Text Available Background: Humans in modern societies expose to substantially elevated levels of electromagnetic field (EMF emissions with different frequencies.The neurobiological effects of EMF have been the subject of debate and intensive research over the past few decades. Therefore, we evaluated the effects of EMF on visual learning and anatomical dimensions of the hippocampus and the prefrontal area (PFA in male Rhesus monkeys. Materials and Methods:In this study, four rhesus monkeys were irradiated by 0.7 microtesla ELF-EMF either at 5 or 30 Hz, 4 h a day, for 30 days. Alterations in visual learning and memory were assessed before and after irradiation phase by using a box designed that cchallenging animals for gaining rewards Also, the monkeys’ brains were scanned by using MRI technique one week before and one week after irradiation. The monkeys were anesthetized by intramuscular injection of ketamine hydrochloride (10–20 mg/kg and xylazine (0.2–0.4 mg/kg, and scanned with a 3-Tesla Magnetom, in axial, sagittal, and coronal planes using T2 weight­ed protocol with a slice thickness of 3 mm. The anatomical changes of hippocampus and the prefrontal area (PFA was measured by volumetric study. Results: Electromagnetic field exposure at a frequency of 30 Hz reduced the number of correct responses in the learning process and delayed memory formation in the two tested monkeys. While, ELF-EMF at 5 Hz had no effect on the visual learning and memory changes. No anatomical changes were found in the prefrontal area and the hippocampus at both frequencies. Conclusion: ELF-EMF irradiation at 30 Hz adversely affected visual learning and memory, pprobably through these changes apply through effects on other factors except changes in brain structure and anatomy.

Use of primary cell cultures to measure the late effects in the skins of rhesus monkeys irradiated with protons

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Cox, A. B.; Wood, D. H.; Lett, J. T.

Previous pilot investigations of the uses of primary cell cultures to study late damage in stem cells of the skin of the New Zealand white (NZW) rabbit and the rhesus monkey /1-3/, have been extended to individual monkeys exposed to 55 MeV protons. Protons of this energy have a larger range in tissue of (~2.6 cm) than the 32 MeV protons (~0.9 cm) to which the animals in our earlier studies had been exposed. Although the primary emphases in the current studies were improvement and simplification in the techniques and logistics of transportation of biopsies to a central analytical facility, comparison of the quantitative measurements obtained thus far for survival of stem cells in the skins from animals irradiated 21 years ago reveals that the effects of both proton energies are similar.

Tahyna virus genetics, infectivity, and immunogenicity in mice and monkeys

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Whitehead Stephen S

2011-03-01

Full Text Available Abstract Background Tahyna virus (TAHV is a human pathogen of the California encephalitis virus (CEV serogroup (Bunyaviridae endemic to Europe, Asia, and Africa. TAHV maintains an enzootic life cycle with several species of mosquito vectors and hares, rabbits, hedgehogs, and rodents serving as small mammal amplifying hosts. Human TAHV infection occurs in summer and early fall with symptoms of fever, headache, malaise, conjunctivitis, pharyngitis, and nausea. TAHV disease can progress to CNS involvement, although unlike related La Crosse virus (LACV, fatalities have not been reported. Human infections are frequent with neutralizing antibodies present in 60-80% of the elderly population in endemic areas. Results In order to determine the genomic sequence of wild-type TAHV, we chose three TAHV isolates collected over a 26-year period from mosquitoes. Here we present the first complete sequence of the TAHV S, M, and L segments. The three TAHV isolates maintained a highly conserved genome with both nucleotide and amino acid sequence identity greater than 99%. In order to determine the extent of genetic relatedness to other members of the CEV serogroup, we compared protein sequences of TAHV with LACV, Snowshoe Hare virus (SSHV, Jamestown Canyon virus (JCV, and Inkoo virus (INKV. By amino acid comparison, TAHV was most similar to SSHV followed by LACV, JCV, and INKV. The sequence of the GN protein is most conserved followed by L, N, GC, NSS, and NSM. In a weanling Swiss Webster mouse model, all three TAHV isolates were uniformly neurovirulent, but only one virus was neuroinvasive. In rhesus monkeys, the virus was highly immunogenic even in the absence of viremia. Cross neutralization studies utilizing monkey immune serum demonstrated that TAHV is antigenically distinct from North American viruses LACV and JCV. Conclusions Here we report the first complete sequence of TAHV and present genetic analysis of new-world viruses, LACV, SSHV, and JCV with old

Promoter methylation and age-related downregulation of Klotho in rhesus monkey.

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King, Gwendalyn D; Rosene, Douglas L; Abraham, Carmela R

2012-12-01

While overall DNA methylation decreases with age, CpG-rich areas of the genome can become hypermethylated. Hypermethylation near transcription start sites typically decreases gene expression. Klotho (KL) is important in numerous age-associated pathways including insulin/IGF1 and Wnt signaling and naturally decreases with age in brain, heart, and liver across species. Brain tissues from young and old rhesus monkeys were used to determine whether epigenetic modification of the KL promoter underlies age-related decreases in mRNA and protein levels of KL. The KL promoter in genomic DNA from brain white matter did not show evidence of oxidation in vivo but did exhibit an increase in methylation with age. Further analysis identified individual CpG motifs across the region of interest with increased methylation in old animals. In vitro methyl modification of these individual cytosine residues confirmed that methylation of the promoter can decrease gene transcription. These results provide evidence that changes in KL gene expression with age may, at least in part, be the result of epigenetic changes to the 5' regulatory region.

Stability of the translocation frequency following whole-body irradiation measured in rhesus monkeys

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Lucas, J. N.; Hill, F. S.; Burk, C. E.; Cox, A. B.; Straume, T.

1996-01-01

Chromosome translocations are persistent indicators of prior exposure to ionizing radiation and the development of 'chromosome painting' to efficiently detect translocations has resulted in a powerful biological dosimetry tool for radiation dose reconstruction. However, the actual stability of the translocation frequency with time after exposure must be measured before it can be used reliably to obtain doses for individuals exposed years or decades previously. Human chromosome painting probes were used here to measure reciprocal translocation frequencies in cells from two tissues of 8 rhesus monkeys (Macaca mulatta) irradiated almost three decades previously. Six of the monkeys were exposed in 1965 to whole-body (fully penetrating) radiation and two were unexposed controls. The primates were irradiated as juveniles to single doses of 0.56, 1.13, 2.00, or 2.25 Gy. Blood lymphocytes (and skin fibroblasts from one individual) were obtained for cytogenetic analysis in 1993, near the end of the animals' lifespans. Results show identical dose-response relationships 28 y after exposure in vivo and immediately after exposure in vitro. Because chromosome aberrations are induced with identical frequencies in vivo and in vitro, these results demonstrate that the translocation frequencies induced in 1965 have not changed significantly during the almost three decades since exposure. Finally, our emerging biodosimetry data for individual radiation workers are now confirming the utility of reciprocal translocations measured by FISH in radiation dose reconstruction.

Comparative anatomy of the arm muscles of the Japanese monkey (Macaca fuscata) with some comments on locomotor mechanics and behavior.

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Aversi-Ferreira, Tales Alexandre; Aversi-Ferreira, Roqueline A G M F; Bretas, Rafael Vieira; Nishimaru, Hiroshi; Nishijo, Hisao

2016-08-01

The anatomical literature on the genus Macaca has focused mainly on the rhesus monkey. However, some aspects in the positional behaviors of the Japanese monkey may be different from those in rhesus monkey, suggesting that the anatomical details of these species are divergent. Four thoracic limbs of Macaca fuscata adults were dissected. The arm muscles in Japanese macaques are more similar to rhesus monkeys and Papio; these characteristics are closer to those of bearded capuchins than apes, indicating more proximity of this genus to New World primates. The anatomical features observed favor quadrupedal locomotor behaviors on the ground and in arboreal environments. Japanese monkeys, rhesus monkeys, and bearded capuchins, which share more primitive characteristics in their arm muscles, present features that favor both arboreal and quadrupedal locomotor behaviors, whereas apes, mainly Pan and Gorilla, which spend more time on the ground, present more quadrupedal specializations. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Immunovirological analyses of chronically simian immunodeficiency virus SIVmnd-1- and SIVmnd-2-infected mandrills (Mandrillus sphinx).

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Apetrei, Cristian; Sumpter, Beth; Souquiere, Sandrine; Chahroudi, Ann; Makuwa, Maria; Reed, Patricia; Ribeiro, Ruy M; Pandrea, Ivona; Roques, Pierre; Silvestri, Guido

2011-12-01

Simian immunodeficiency virus (SIV) infection in African nonhuman primate (NHP) natural hosts is usually nonpathogenic, despite high levels of virus replication. We have previously shown that chronic SIV infection in sooty mangabeys (SMs) and African green monkeys (AGMs) is associated with low levels of immune activation and bystander T cell apoptosis. To compare these features with those observed in another natural host, the mandrill (MND), we conducted a cross-sectional survey of the 23 SIV-infected and 25 uninfected MNDs from the only semifree colony of mandrills available worldwide. Viral loads (VLs) were determined and phenotypic and functional analysis of peripheral blood- and lymph node-derived lymphocytes was performed. We found that mandrills chronically infected with SIVmnd-1 or SIVmnd-2 have similar levels of viral replication, and we observed a trend toward lower CD4+ T cell counts in chronically SIVmnd-2-infected MNDs than SIVmnd-1-infected MNDs. No correlation between CD4+ T cell counts and VLs in SIV-infected MNDs could be established. Of note, the levels of T cell activation, proliferation, and apoptosis were comparable between SIVmnd-1- and SIVmnd-2-infected MNDs and to those observed in uninfected animals, with the only exception being an increase in tumor necrosis factor alpha-producing CD8+ T cells in SIVmnd-2-infected MNDs. Overall, these findings recapitulate previous observations in SIV-infected SMs and AGMs and lend further evidence to the hypothesis that low levels of immune activation protect natural SIV hosts from disease progression.

Simian immunodeficiency virus infection induces severe loss of intestinal central memory T cells which impairs CD4+ T-cell restoration during antiretroviral therapy.

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Verhoeven, D; Sankaran, S; Dandekar, S

2007-08-01

Simian immunodeficiency virus (SIV) infection leads to severe loss of intestinal CD4(+) T cells and, as compared to peripheral blood, restoration of these cells is slow during antiretroviral therapy (ART). Mechanisms for this delay have not been examined in context of which specific CD4(+) memory subsets or lost and fail to regenerate during ART. Fifteen rhesus macaques were infected with SIV, five of which received ART (FTC/PMPA) for 30 weeks. Viral loads were measured by real-time PCR. Flow cytometric analysis determined changes in T-cell subsets and their proliferative state. Changes in proliferative CD4(+) memory subsets during infection accelerated their depletion. This reduced the central memory CD4(+) T-cell pool and contributed to slow CD4(+) T-cell restoration during ART. There was a lack of restoration of the CD4(+) central memory and effector memory T-cell subsets in gut-associated lymphoid tissue during ART, which may contribute to the altered intestinal T-cell homeostasis in SIV infection.

Rhesus monkeys (Macaca mulatta) show robust primacy and recency in memory for lists from small, but not large, image sets.

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Basile, Benjamin M; Hampton, Robert R

2010-02-01

The combination of primacy and recency produces a U-shaped serial position curve typical of memory for lists. In humans, primacy is often thought to result from rehearsal, but there is little evidence for rehearsal in nonhumans. To further evaluate the possibility that rehearsal contributes to primacy in monkeys, we compared memory for lists of familiar stimuli (which may be easier to rehearse) to memory for unfamiliar stimuli (which are likely difficult to rehearse). Six rhesus monkeys saw lists of five images drawn from either large, medium, or small image sets. After presentation of each list, memory for one item was assessed using a serial probe recognition test. Across four experiments, we found robust primacy and recency with lists drawn from small and medium, but not large, image sets. This finding is consistent with the idea that familiar items are easier to rehearse and that rehearsal contributes to primacy, warranting further study of the possibility of rehearsal in monkeys. However, alternative interpretations are also viable and are discussed. Copyright 2009 Elsevier B.V. All rights reserved.

Experimental infection of macaques with a wild water bird-derived highly pathogenic avian influenza virus (H5N1.

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Tomoko Fujiyuki

Full Text Available Highly pathogenic avian influenza virus (HPAIV continues to threaten human health. Non-human primate infection models of human influenza are desired. To establish an animal infection model with more natural transmission and to determine the pathogenicity of HPAIV isolated from a wild water bird in primates, we administered a Japanese isolate of HPAIV (A/whooper swan/Hokkaido/1/2008, H5N1 clade 2.3.2.1 to rhesus and cynomolgus monkeys, in droplet form, via the intratracheal route. Infection of the lower and upper respiratory tracts and viral shedding were observed in both macaques. Inoculation of rhesus monkeys with higher doses of the isolate resulted in stronger clinical symptoms of influenza. Our results demonstrate that HPAIV isolated from a water bird in Japan is pathogenic in monkeys by experimental inoculation, and provide a new method for HPAIV infection of non-human primate hosts, a good animal model for investigation of HPAIV pathogenicity.

Responses of free-ranging rhesus monkeys to a natural form of social separation. I. Parallels with mother-infant separation in captivity.

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Berman, C M; Rasmussen, K L; Suomi, S J

1994-08-01

Observations of 23 free-ranging rhesus monkey infants on Cayo Santiago, Puerto Rico, indicated that mothers' first postpartum estrous periods were marked by large increases in the amount of time infants were separated from their mothers, by disturbances in mother-infant relationships, and by increases in infant distress behavior. When their mothers resumed mating, most infants showed signs of agitation; a few briefly showed indications of depression. Male infants responded to their mothers' resumption of mating by playing more, whereas females engaged in less play and more allogrooming. The results suggest (a) that basic parallels exist between the behavioral responses of rhesus infants to their mothers' resumption of mating in the field and to forcible separation from their mothers in captivity and (b) that early separation experiences may play a role in the normal development or manifestation of sex differences in behavior.

ABO, rhesus blood groups and transfusion-transmitted infections ...

African Journals Online (AJOL)

Background: Few studies focused on the study of blood groups in Gabon. This study aimed to determine the phenotypic frequency of ABO and Rhesus antigens in blood donors of Libreville and to assess the association between ABO blood groups and transfusion-transmitted infections. Materials and Methods: The study of ...

High-throughput gene expression profiling indicates dysregulation of intestinal cell cycle mediators and growth factors during primary simian immunodeficiency virus infection

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George, Michael D; Sankaran, Sumathi; Reay, Elizabeth; Gelli, Angie C; Dandekar, Satya

2003-07-20

During primary simian immunodeficiency virus (SIV) infection, CD4+ T cells are severely depleted in gut-associated lymphoid tissue (GALT), while CD8+ T-cell numbers dramatically increase. To gain an understanding of the molecular basis of this disruption in T-cell homeostasis, host gene expression was monitored in longitudinal jejunum tissue biopsies from SIV-infected rhesus macaques by DNA microarray analysis. Transcription of cyclin E1, CDC2, retinoblastoma, transforming growth factor (TGF), fibroblast growth factor (FGF), and interleukin-2 was repressed while cyclins B1 and D2 and transcription factor E2F were upregulated, indicating a complex dysregulation of growth and proliferation within the intestinal mucosa. Innate, cell-mediated, and humoral immune responses were markedly upregulated in animals that significantly reduced their viral loads and retained more intestinal CD4+ T cells. We conclude that the alterations in intestinal gene expression during primary SIV infection were characteristic of a broad-range immune response, and reflective of the efficacy of viral suppression.

High-throughput gene expression profiling indicates dysregulation of intestinal cell cycle mediators and growth factors during primary simian immunodeficiency virus infection

International Nuclear Information System (INIS)

George, Michael D.; Sankaran, Sumathi; Reay, Elizabeth; Gelli, Angie C.; Dandekar, Satya

2003-01-01

During primary simian immunodeficiency virus (SIV) infection, CD4+ T cells are severely depleted in gut-associated lymphoid tissue (GALT), while CD8+ T-cell numbers dramatically increase. To gain an understanding of the molecular basis of this disruption in T-cell homeostasis, host gene expression was monitored in longitudinal jejunum tissue biopsies from SIV-infected rhesus macaques by DNA microarray analysis. Transcription of cyclin E1, CDC2, retinoblastoma, transforming growth factor (TGF), fibroblast growth factor (FGF), and interleukin-2 was repressed while cyclins B1 and D2 and transcription factor E2F were upregulated, indicating a complex dysregulation of growth and proliferation within the intestinal mucosa. Innate, cell-mediated, and humoral immune responses were markedly upregulated in animals that significantly reduced their viral loads and retained more intestinal CD4+ T cells. We conclude that the alterations in intestinal gene expression during primary SIV infection were characteristic of a broad-range immune response, and reflective of the efficacy of viral suppression

Sequential priming with simian immunodeficiency virus (SIV) DNA vaccines, with or without encoded cytokines, and a replicating adenovirus-SIV recombinant followed by protein boosting does not control a pathogenic SIVmac251 mucosal challenge.

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Demberg, Thorsten; Boyer, Jean D; Malkevich, Nina; Patterson, L Jean; Venzon, David; Summers, Ebonita L; Kalisz, Irene; Kalyanaraman, V S; Lee, Eun Mi; Weiner, David B; Robert-Guroff, Marjorie

2008-11-01

Previously, combination DNA/nonreplicating adenovirus (Ad)- or poxvirus-vectored vaccines have strongly protected against SHIV(89.6P), DNAs expressing cytokines have modulated immunity elicited by DNA vaccines, and replication-competent Ad-recombinant priming and protein boosting has strongly protected against simian immunodeficiency virus (SIV) challenge. Here we evaluated a vaccine strategy composed of these promising components. Seven rhesus macaques per group were primed twice with multigenic SIV plasmid DNA with or without interleukin-12 (IL-12) DNA or IL-15 DNA. After a multigenic replicating Ad-SIV immunization, all groups received two booster immunizations with SIV gp140 and SIV Nef protein. Four control macaques received control DNA plasmids, empty Ad vector, and adjuvant. All vaccine components were immunogenic, but the cytokine DNAs had little effect. Macaques that received IL-15-DNA exhibited higher peak anti-Nef titers, a more rapid anti-Nef anamnestic response postchallenge, and expanded CD8(CM) T cells 2 weeks postchallenge compared to the DNA-only group. Other immune responses were indistinguishable between groups. Overall, no protection against intrarectal challenge with SIV(mac251) was observed, although immunized non-Mamu-A*01 macaques as a group exhibited a statistically significant 1-log decline in acute viremia compared to non-Mamu-A*01 controls. Possible factors contributing to the poor outcome include administration of cytokine DNAs to sites different from the Ad recombinants (intramuscular and intratracheal, respectively), too few DNA priming immunizations, a suboptimal DNA delivery method, failure to ensure delivery of SIV and cytokine plasmids to the same cell, and instability and short half-life of the IL-15 component. Future experiments should address these issues to determine if this combination approach is able to control a virulent SIV challenge.

Multiple antibody targets on herpes B glycoproteins B and D identified by screening sera of infected rhesus macaques with peptide microarrays.

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Sven-Kevin Hotop

Full Text Available Herpes B virus (or Herpesvirus simiae or Macacine herpesvirus 1 is endemic in many populations of macaques, both in the wild and in captivity. The virus elicits only mild clinical symptoms (if any in monkeys, but can be transmitted by various routes, most commonly via bites, to humans where it causes viral encephalitis with a high mortality rate. Hence, herpes B constitutes a considerable occupational hazard for animal caretakers, veterinarians and laboratory personnel. Efforts are therefore being made to reduce the risk of zoonotic infection and to improve prognosis after accidental exposure. Among the measures envisaged are serological surveillance of monkey colonies and specific diagnosis of herpes B zoonosis against a background of antibodies recognizing the closely related human herpes simplex virus (HSV. 422 pentadecapeptides covering, in an overlapping fashion, the entire amino acid sequences of herpes B proteins gB and gD were synthesized and immobilized on glass slides. Antibodies present in monkey sera that bind to subsets of the peptide collection were detected by microserological techniques. With 42 different rhesus macaque sera, 114 individual responses to 18 different antibody target regions (ATRs were recorded, 17 of which had not been described earlier. This finding may pave the way for a peptide-based, herpes B specific serological diagnostic test.

Use of radiolabeled monoclonal anti-B1 antibody for B lymphocyte imaging in Rhesus monkeys

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Letvin, N.L.; Zalutsky, M.R.; Chalifoux, L.V.; Atkins, H.L.

1987-01-01

Imaging tissues rich in B lymphocytes in man using a radiolabeled monoclonal anti-B cell antibody would be extremely useful in the clinical staging of non-Hodgkins lymphomas. Studies were done in rhesus monkeys using radiolabeled monoclonal anti-B1 antibody to determine the feasibility of such an approach. Immunohistologic studies demonstrated that infused monoclonal anti-B1 binds in vivo with specificity to B cells in lymph nodes and spleen. The kinetics of clearance of 131 I-labeled anti-B1 were determined. The B lymphocyte-rich spleen could be readily visualized by gamma camera scanning without significant background and without the need for image intensification or blood background subtraction techniques. These data support the feasibility of using anti-B1 for staging B cell lymphomas in man. (author)

Seroprevalence of simian immunodeficiency virus in wild and captive born Sykes' monkeys (Cercopithecus mitis in Kenya

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Otsyula Moses G

2004-10-01

Full Text Available Abstract Background The Sykes' monkey and related forms (Cercopithecus mitis make up an abundant, widespread and morphologically diverse species complex in eastern Africa that naturally harbors a distinct simian immunodeficiency virus (SIVsyk. We carried out a retrospective serological survey of SIV infection from both wild and captive Sykes' monkeys from Kenya. We compared two commercially available, cross-reactive ELISA tests using HIV antigens with a novel SIVsyk antigen-specific Western blot assay and analyzed the data by origin, subspecies, age and sex. Results The SIVsyk antigen-specific Western blot assay detected more serum samples as positive than either of the cross-reactive ELISA assays. Using this assay, we found that seroprevalence is higher than previously reported, but extremely variable in wild populations (from 0.0 to 90.9%. Females were infected more often than males in both wild and captive populations. Seropositive infants were common. However, no seropositive juveniles were identified. Conclusion We have developed a specific and sensitive Western blot assay for anti-SIVsyk antibody detection. Sykes' monkeys are commonly infected with SIVsyk, but with extremely variable prevalence in the wild. Higher infection prevalence in females suggests predominantly sexual transmission. High infection prevalence in infants, but none in juveniles, suggests maternal antibodies, but little or no vertical transmission.

Monkey-based research on human disease: the implications of genetic differences.

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Bailey, Jarrod

2014-11-01

Assertions that the use of monkeys to investigate human diseases is valid scientifically are frequently based on a reported 90-93% genetic similarity between the species. Critical analyses of the relevance of monkey studies to human biology, however, indicate that this genetic similarity does not result in sufficient physiological similarity for monkeys to constitute good models for research, and that monkey data do not translate well to progress in clinical practice for humans. Salient examples include the failure of new drugs in clinical trials, the highly different infectivity and pathology of SIV/HIV, and poor extrapolation of research on Alzheimer's disease, Parkinson's disease and stroke. The major molecular differences underlying these inter-species phenotypic disparities have been revealed by comparative genomics and molecular biology - there are key differences in all aspects of gene expression and protein function, from chromosome and chromatin structure to post-translational modification. The collective effects of these differences are striking, extensive and widespread, and they show that the superficial similarity between human and monkey genetic sequences is of little benefit for biomedical research. The extrapolation of biomedical data from monkeys to humans is therefore highly unreliable, and the use of monkeys must be considered of questionable value, particularly given the breadth and potential of alternative methods of enquiry that are currently available to scientists. 2014 FRAME.

Too good to be true: rhesus monkeys react negatively to better-than-expected offers.

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Emily J Knight

Full Text Available To succeed in a dynamically changing world, animals need to predict their environments. Humans, in fact, exhibit such a strong desire for consistency that one of the most well-established findings in social psychology is the effort people make to maintain consistency among their beliefs, attitudes, and behavior. However, displeasure with unpredictability leads to a potential paradox, because a positive outcome that exceeds one's expectations often leads to increased subjective value and positive affect, not the opposite. We tested the hypothesis that two evolutionarily-conserved evaluation processes underlie goal-directed behavior: (1 consistency, concerned with prediction errors, and (2 valuation, concerned with outcome utility. Rhesus monkeys (Macaca mulatta viewed a food item and then were offered an identical, better, or worse food, which they could accept or reject. The monkeys ultimately accepted all offers, attesting to the influence of the valuation process. However, they were slower to accept the unexpected offers, and they exhibited aversive reactions, especially to the better-than-expected offers, repeatedly turning their heads and looking away before accepting the food item. Our findings (a provide evidence for two separable evaluation processes in primates, consistency and value assessment, (b reveal a direct relationship between consistency assessment and emotional processes, and (c show that our wariness with events that are much better than expected is shared with other social primates.

(Ir)rational choices of humans, rhesus macaques, and capuchin monkeys in dynamic stochastic environments.

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Watzek, Julia; Brosnan, Sarah F

2018-05-28

Human and animal decision-making is known to violate rational expectations in a variety of contexts. Previous models suggest that statistical structures of real-world environments can favor such seemingly irrational behavior, but this has not been tested empirically. We tested 16 capuchin monkeys, seven rhesus monkeys, and 30 humans in a computerized experiment that implemented such stochastic environments. Subjects chose from among up to three options of different value that disappeared and became available again with different probabilities. All species overwhelmingly chose transitively (A > B > C) in the control condition, where doing so maximized overall gain. Most subjects also adhered to transitivity in the test condition, where it was suboptimal, but ultimately led to negligible losses compared to the optimal, non-transitive strategy. We used a modelling approach to show that differences in temporal discounting may account for this pattern of choices on a proximate level. Specifically, when short- and long-term goals are valued similarly, near-optimal decision rules can map onto rational choice principles. Such cognitive shortcuts have been argued to have evolved to preserve mental resources without sacrificing good decision-making, and here we provide evidence that these heuristics can provide almost identical outcomes even in situations in which they lead to suboptimal choices. Copyright © 2018 Elsevier B.V. All rights reserved.

SURGICAL INTERVENTION AND ACCOMMODATIVE RESPONSES: I. CENTRIPETAL CILIARY BODY, CAPSULE AND LENS MOVEMENT IN RHESUS MONKEYS OF VARYING AGE

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Croft, Mary Ann; Mcdonald, Jared P.; James, Rebecca J.; Heatley, Gregg A.; Lin, Ting-Li; Lütjen-Drecoll, Elke; Kaufman, Paul L.

2009-01-01

Purpose To determine how surgically altering the normal relationship between the lens and the ciliary body in rhesus monkeys affects centripetal ciliary body and lens movement. Methods In 18 rhesus monkey eyes (aged 6–27 years), accommodation was induced before and after surgery by electrical stimulation of the Edinger-Westphal (E–W) nucleus. Accommodative amplitude was measured by coincidence refractometry. Goniovideography was performed before and after intra- and extra-capsular lens extraction (ICLE, ECLE) and anterior regional zonulolysis. Centripetal lens/capsule movements, centripetal ciliary process (CP) movements, and circumlental space were measured by computerized image analysis of the goniovideography images. Results Centripetal accommodative CP and capsule movement increased in velocity and amplitude post-ECLE compared to pre-ECLE regardless of age (n=5). The presence of the lens substance retarded capsule movement by ~21% in the young eyes and by ~62% in the older eyes. Post-ICLE compared to pre-ICLE centripetal accommodative CP movement was dampened in all eyes in which the anterior vitreous was disturbed (n=7), but not in eyes in which the anterior vitreous was left intact (n=2). Following anterior regional zonulolysis (n=4), lens position shifted toward the lysed quadrant during accommodation. Conclusions The presence of the lens substance, capsule zonular attachments, and Wiegers ligament may play a role in centripetal CP movement. The capsule is still capable of centripetal movement in the older eye (although at a reduced capacity) and may have the ability to produce ~6 diopters of accommodation in the presence of a normal young crystalline lens or a similar surrogate. PMID:18552393

Interaction between Mu and Delta Opioid Receptor Agonists in an Assay of Capsaicin-Induced Thermal Allodynia in Rhesus Monkeys

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S. Stevens Negus

2012-01-01

Full Text Available Delta opioid agonists enhance antinociceptive effects of mu-opioid agonists in many preclinical assays of acute nociception, but delta/mu interactions in preclinical models of inflammation-associated pain have not been examined. This study examined interactions between the delta agonist SNC80 [(+-4-[(αR-α-((2S,5R-4-allyl-2,5-dimethyl-1-piperazinyl-3-methoxybenzyl]-N,N-diethylbenzamide] and the mu agonist analgesics methadone, morphine, and nalbuphine in an assay of capsaicin-induced thermal allodynia in rhesus monkeys. Thermal allodynia was produced by topical application of capsaicin to the tail. Antiallodynic effects of methadone, morphine, and nalbuphine were evaluated alone or in combination with fixed proportions of SNC80 identical to proportions previously shown to enhance acute thermal antinociceptive effects of these mu agonists in rhesus monkeys (0.9 : 1 SNC80/methadone; 0.29 : 1 SNC80/morphine; 3.6 : 1 SNC80/nalbuphine. Methadone, morphine, and nalbuphine each produced dose-dependent antiallodynia. SNC80 produced partial antiallodynia up to the highest dose tested (5.6 mg/kg. SNC80 produced a modest, enantioselective, and naltrindole-reversible enhancement of methadone-induced antiallodynia. However, SNC80 did not enhance morphine antiallodynia and only weakly enhanced nalbuphine antiallodynia. Overall, SNC80 produced modest or no enhancement of the antiallodynic effects of the three mu agonists evaluated. These results suggest that delta agonist-induced enhancement of mu agonist antiallodynia may be weaker and less reliable than previously demonstrated enhancement of mu agonist acute thermal nociception.

Genetic polymorphisms of drug-metabolizing cytochrome P450 enzymes in cynomolgus and rhesus monkeys and common marmosets in preclinical studies for humans.

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Uno, Yasuhiro; Uehara, Shotaro; Yamazaki, Hiroshi

2017-12-23

Cynomolgus monkeys (Macaca fascicularis, Old World Monkeys) and common marmosets (Callithrix jacchus, New World Monkeys) have been widely, and expectedly, used as non-human primate models in drug development studies. Major drug-metabolizing cytochrome P450 (P450) enzymes information is now available that supports these primate species as animal models, and it is established that multiple forms of cynomolgus monkey and common marmoset P450 enzymes have generally similar substrate recognition functionality to human P450 enzymes. This research update provides information on genetic polymorphisms of P450 enzymes in cynomolgus monkey and common marmoset like human P450 enzymes. Information on rhesus monkeys (Macaca mulatta), another macaque species used in drug metabolism studies, is also included for comparison. Among a variety of cynomolgus monkey P450 variants investigated, typical examples include individual pharmacokinetic data for efavirenz and R-warfarin associated with cynomolgus monkey P450 2C9 (formerly 2C43) and 2C19 (2C75) variants, respectively, and for R-omeprazole and S-warfarin associated with marmoset P450 2C19 variants. These findings provide a foundation for understanding the individual pharmacokinetic and toxicological results in non-human primates as preclinical models and will help to further support understanding of molecular mechanisms of human P450 function. In addition to these polymorphic P450 enzymes, effects of aging on some drug clearances mediated by cynomolgus monkey and common marmoset P450 enzymes were found in elder animals or animals pretreated with rifampicin. This review describes genetic and acquired individual differences in cynomolgus monkey and common marmoset P450 enzymes involved in drug oxidation associated with pharmacological and/or toxicological effects. Copyright © 2017 Elsevier Inc. All rights reserved.

Behavioral inhibition in rhesus monkeys (Macaca mulatta is related to the airways response, but not immune measures, commonly associated with asthma.

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Katie Chun

Full Text Available Behavioral inhibition reflects a disposition to react warily to novel situations, and has been associated with atopic diseases such as asthma. Retrospective work established the relationship between behavioral inhibition in rhesus monkeys (Macaca mulatta and airway hyperresponsiveness, but not atopy, and the suggestion was made that behavioral inhibition might index components of asthma that are not immune-related. In the present study, we prospectively examined the relationship between behavioral inhibition and airway hyperresponsiveness, and whether hormonal and immune measures often associated with asthma were associated with behavioral inhibition and/or airway hyperresponsiveness. In a sample of 49 yearling rhesus monkeys (mean=1.25 years, n=24 behaviorally inhibited animals, we measured in vitro cytokine levels (IL-4, IL-10, IL-12, IFN-γ in response to stimulation, as well as peripheral blood cell percentages, cortisol levels, and percentage of regulatory T-cells (CD3+CD4+CD25+FOXP3+. Airway reactivity was assessed using an inhaled methacholine challenge. Bronchoalveolar lavage was performed and the proportion of immune cells was determined. Behaviorally inhibited monkeys had airway hyperresponsiveness as indicated by the methacholine challenge (p=0.031, confirming our earlier retrospective result. Airway hyperresponsiveness was also associated with lower lymphocyte percentages in lavage fluid and marginally lower plasma cortisol concentrations. However, none of the tested measures was significantly related to both behavioral inhibition and airway hyperresponsiveness, and so could not mediate their relationship. Airway hyperresponsiveness is common to atopic and non-atopic asthma and behavioral inhibition has been related to altered autonomic activity in other studies. Our results suggest that behavioral inhibition might index an autonomically mediated reactive airway phenotype, and that a variety of stimuli (including inflammation within

Placental transfer and metabolism of 17 alpha-ethynylestradiol-17 beta and estradiol-17 beta in the rhesus monkey

International Nuclear Information System (INIS)

Slikker, W. Jr.; Bailey, J.R.; Newport, D.; Lipe, G.W.; Hill, D.E.

1982-01-01

The synthetic estrogen component of many oral contraceptives, 17 alpha-ethynylestradiol-17 beta (EE2) and the naturally occurring estrogen, estradiol-17 beta (E2) were studied in four pregnant rhesus monkeys (71% term: 108-121 days gestational age). Under ketamine anesthesia, catheters were implanted in the maternal femoral artery and fetal interplacental artery. After simultaneous i.v. administration of [ 3 H]EE2-[ 14 C]E2 to the maternal animal, serial blood samples were drawn from both mother and fetus. The estrogens and metabolites were identified and quantified by the comigration of radioactivity with reference standards in several high-performance liquid chromatography systems and subsequent selective enzyme hydrolysis of the conjugates. Only estrone (E1), E1 sulfate, EE2 and EE2-3 sulfate were observed in the fetal circulation, whereas the major radiolabeled compounds in the maternal circulation consisted of the above plus E2, E1 glucuronide and EE2-3 glucuronide. In order to determine whether the placenta could convert E2 to its metabolite E1, the placentas of three term rhesus monkeys were perfused in situ via the umbilical artery with 120 ml (15 ml/min) of Hanks' balanced salt solution (pH 7.4) containing [ 3 H]E2. High-performance liquid chromatographic analysis of umbilical vein samples revealed that 96% of the E2 was metabolized to E1. These studies indicate that the placenta can metabolize the potent naturally occurring estrogen E2 to the less potent E1. In contrast, the synthetic estrogen EE2 does not undergo this placental metabolic conversion and thus enters the fetal circulation as the parent compound

Neurovirulence of yellow fever 17DD vaccine virus to rhesus monkeys

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Marchevsky, Renato S.; Freire, Marcos S.; Coutinho, Evandro S.F.; Galler, Ricardo

2003-01-01

The yellow fever 17D virus is attenuated and used for human vaccination. Two of its substrains, 17D-204 and 17DD, are used for vaccine production. One of the remarkable properties of this vaccine is limited viral replication in the host but with significant dissemination of the viral mass, yielding a robust and long-lived neutralizing antibody response. The vaccine has excellent records of efficacy and safety and is cheap, used as a single dose, and there are well-established production methodology and quality control procedures which include the monkey neurovirulence test (MNTV). The present study aims at a better understanding of YF 17DD virus attenuation and immunogenicity in the MNVT with special emphasis on viremia, seroconversion, clinical and histological lesions scores, and their intrinsic variability across the tests. Several MNVTs were performed using the secondary seed lot virus 17DD 102/84 totaling 49 rhesus monkeys. Viremia was never higher than the accepted limits established in international requirements, and high levels of neutralizing antibodies were observed in all animals. None of the animals showed visceral lesions. We found that the clinical scores for the same virus varied widely across the tests. There was a direct correlation between the clinical scores in animals with clinical signs of encephalitis and a higher degree of central nervous system (CNS) histological lesions, with an increase of lesions in areas of the CNS such as the substantia nigra, nucleus caudatus, intumescentia cervicalis, and intumescentia ventralis. The histological scores were shown to be less prone to individual variations and had a more homogeneous value distribution among the tests. Since 17DD 102/84 seed virus has been used for human vaccine production and immunization for 16 years with the vaccine being safe and efficacious, it demonstrates that the observed variations across the MNVTs do not influence its effect on humans

High-throughput profiling of anti-glycan humoral responses to SIV vaccination and challenge.

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Christopher T Campbell

Full Text Available Recent progress toward an HIV vaccine highlights both the potential of vaccines to end the AIDS pandemic and the need to boost efficacy by incorporating additional vaccine strategies. Although many aspects of the immune response can contribute to vaccine efficacy, the key factors have not been defined fully yet. A particular area that may yield new insights is anti-glycan immune responses, such as those against the glycan shield that HIV uses to evade the immune system. In this study, we used glycan microarray technology to evaluate anti-glycan antibody responses induced by SIV vaccination and infection in a non-human primate model of HIV infection. This comprehensive profiling of circulating anti-glycan antibodies found changes in anti-glycan antibody levels after both vaccination with the Ad5hr-SIV vaccine and SIV infection. Notably, SIV infection produced generalized declines in anti-glycan IgM antibodies in a number of animals. Additionally, some infected animals generated antibodies to the Tn antigen, which is a cryptic tumor-associated antigen exposed by premature termination of O-linked glycans; however, the Ad5hr-SIV vaccine did not induce anti-Tn IgG antibodies. Overall, this study demonstrates the potential contributions that glycan microarrays can make for HIV vaccine development.

Microarray profiling of progesterone-regulated endometrial genes during the rhesus monkey secretory phase

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Okulicz William C

2004-07-01

Full Text Available Abstract Background In the endometrium the steroid hormone progesterone (P, acting through its nuclear receptors, regulates the expression of specific target genes and gene networks required for endometrial maturation. Proper endometrial maturation is considered a requirement for embryo implantation. Endometrial receptivity is a complex process that is spatially and temporally restricted and the identity of genes that regulate receptivity has been pursued by a number of investigators. Methods In this study we have used high density oligonucleotide microarrays to screen for changes in mRNA transcript levels between normal proliferative and adequate secretory phases in Rhesus monkey artificial menstrual cycles. Biotinylated cRNA was prepared from day 13 and days 21–23 of the reproductive cycle and transcript levels were compared by hybridization to Affymetrix HG-U95A arrays. Results Of ~12,000 genes profiled, we identified 108 genes that were significantly regulated during the shift from a proliferative to an adequate secretory endometrium. Of these genes, 39 were up-regulated at days 21–23 versus day 13, and 69 were down-regulated. Genes up-regulated in P-dominant tissue included: secretoglobin (uteroglobin, histone 2A, polo-like kinase (PLK, spermidine/spermine acetyltransferase 2 (SAT2, secretory leukocyte protease inhibitor (SLPI and metallothionein 1G (MT1G, all of which have been previously documented as elevated in the Rhesus monkey or human endometrium during the secretory phase. Genes down-regulated included: transforming growth factor beta-induced (TGFBI or BIGH3, matrix metalloproteinase 11 (stromelysin 3, proenkephalin (PENK, cysteine/glycine-rich protein 2 (CSRP2, collagen type VII alpha 1 (COL7A1, secreted frizzled-related protein 4 (SFRP4, progesterone receptor membrane component 1 (PGRMC1, chemokine (C-X-C ligand 12 (CXCL12 and biglycan (BGN. In addition, many novel/unknown genes were also identified. Validation of array data

Differential Responding by Rhesus Monkeys (Macaca mulatta and Humans (Homo sapiens to Variable Outcomes in the Assurance Game

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Audrey E. Parrish

2014-08-01

Full Text Available Behavioral flexibility in how one responds to variable partner play can be examined using economic coordination games in which subjects play against a variety of partners and therefore may need to alter their behavior to produce the highest payoff. But how do we study this behavioral flexibility once players have settled on a response? Here, we investigated how responding by rhesus monkeys (Macaca mulatta and humans (Homo sapiens playing a computerized single-player version of a coordination game, the Assurance game, changed as a function of the variable responses (Stag/Hare generated by multiple simulations (SIMs. We were interested in whether individuals could track and differentially respond to changing frequencies of Stag and Hare play by the SIMs, especially with regard to the payoff dominant (Stag-Stag outcome, something that could not be done with real partners as they quickly settled on the Stag response. For both monkeys and humans, there was a linear relationship between proportion of Stag play by the subject and the likelihood of the Stag choice by the SIM such that both species increased their use of Stag as the SIM increased its use of the Stag response. However, humans more closely matched their proportion of Stag responses to that of the SIM, whereas monkeys adopted a different, but equally effective, strategy of exploiting the higher-paying Stag alternative. These results suggest that monkeys and humans demonstrate sensitivity to a dynamic game environment in which they encounter variable contingencies for the same response options, although they may employ different strategies to maximize reward.

Modification of a loop sequence between α-helices 6 and 7 of virus capsid (CA protein in a human immunodeficiency virus type 1 (HIV-1 derivative that has simian immunodeficiency virus (SIVmac239 vif and CA α-helices 4 and 5 loop improves replication in cynomolgus monkey cells

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Adachi Akio

2009-08-01

Full Text Available Abstract Background Human immunodeficiency virus type 1 (HIV-1 productively infects only humans and chimpanzees but not cynomolgus or rhesus monkeys while simian immunodeficiency virus isolated from macaque (SIVmac readily establishes infection in those monkeys. Several HIV-1 and SIVmac chimeric viruses have been constructed in order to develop an animal model for HIV-1 infection. Construction of an HIV-1 derivative which contains sequences of a SIVmac239 loop between α-helices 4 and 5 (L4/5 of capsid protein (CA and the entire SIVmac239 vif gene was previously reported. Although this chimeric virus could grow in cynomolgus monkey cells, it did so much more slowly than did SIVmac. It was also reported that intrinsic TRIM5α restricts the post-entry step of HIV-1 replication in rhesus and cynomolgus monkey cells, and we previously demonstrated that a single amino acid in a loop between α-helices 6 and 7 (L6/7 of HIV type 2 (HIV-2 CA determines the susceptibility of HIV-2 to cynomolgus monkey TRIM5α. Results In the study presented here, we replaced L6/7 of HIV-1 CA in addition to L4/5 and vif with the corresponding segments of SIVmac. The resultant HIV-1 derivatives showed enhanced replication capability in established T cell lines as well as in CD8+ cell-depleted primary peripheral blood mononuclear cells from cynomolgus monkey. Compared with the wild type HIV-1 particles, the viral particles produced from a chimeric HIV-1 genome with those two SIVmac loops were less able to saturate the intrinsic restriction in rhesus monkey cells. Conclusion We have succeeded in making the replication of simian-tropic HIV-1 in cynomolgus monkey cells more efficient by introducing into HIV-1 the L6/7 CA loop from SIVmac. It would be of interest to determine whether HIV-1 derivatives with SIVmac CA L4/5 and L6/7 can establish infection of cynomolgus monkeys in vivo.

Social relevance drives viewing behavior independent of low-level salience in rhesus macaques

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James Andrew Solyst

2014-11-01

Full Text Available Quantifying attention to social stimuli during the viewing of complex social scenes with eye tracking has proven to be a sensitive method in the diagnosis of autism spectrum disorders years before average clinical diagnosis. Rhesus macaques provide an ideal model for understanding the mechanisms underlying social viewing behavior, but to date no comparable behavioral task has been developed for use in monkeys. Using a novel scene-viewing task, we monitored the gaze of three rhesus macaques while they freely viewed well-controlled composed social scenes and analyzed the time spent viewing objects and monkeys. In each of six behavioral sessions, monkeys viewed a set of 90 images (540 unique scenes with each image presented twice. In two-thirds of the repeated scenes, either a monkey or an object was replaced with a novel item (manipulated scenes. When viewing a repeated scene, monkeys made longer fixations and shorter saccades, shifting from a rapid orienting to global scene contents to a more local analysis of fewer items. In addition to this repetition effect, in manipulated scenes, monkeys demonstrated robust memory by spending more time viewing the replaced items. By analyzing attention to specific scene content, we found that monkeys strongly preferred to view conspecifics and that this was not related to their salience in terms of low-level image features. A model-free analysis of viewing statistics found that monkeys that were viewed earlier and longer had direct gaze and redder sex skin around their face and rump, two important visual social cues. These data provide a quantification of viewing strategy, memory and social preferences in rhesus macaques viewing complex social scenes, and they provide an important baseline with which to compare to the effects of therapeutics aimed at enhancing social cognition.

Early depletion of proliferating B cells of germinal center in rapidly progressive simian immunodeficiency virus infection

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Zhang Zhiqiang; Casimiro, Danilo R.; Schleif, William A.; Chen, Minchun; Citron, Michael; Davies, Mary-Ellen; Burns, Janine; Liang, Xiaoping; Fu, Tong-Ming; Handt, Larry; Emini, Emilio A.; Shiver, John W.

2007-01-01

Lack of virus specific antibody response is commonly observed in both HIV-1-infected humans and SIV-infected monkeys with rapid disease progression. However, the mechanisms underlying this important observation still remain unclear. In a titration study of a SIVmac239 viral stock, three out of six animals with viral inoculation rapidly progressed to AIDS within 5 months. Unexpectedly, there was no obvious depletion of CD4 + T cells in both peripheral and lymph node (LN) compartments in these animals. Instead, progressive depletion of proliferating B cells and disruption of the follicular dendritic cell (FDC) network in germinal centers (GC) was evident in the samples collected at as early as 20 days after viral challenge. This coincided with undetectable, or weak and transient, virus-specific antibody responses over the course of infection. In situ hybridization of SIV RNA in the LN samples revealed a high frequency of SIV productively infected cells and large amounts of accumulated viral RNA in the GCs in these animals. Early severe depletion of GC proliferating B cells and disruption of the FDC network may thus result in an inability to mount a virus-specific antibody response in rapid progressors, which has been shown to contribute to accelerated disease progression of SIV infection

Identification of UGT2B9*2 and UGT2B33 isolated from female rhesus monkey liver.

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Dean, Brian; Arison, Byron; Chang, Steve; Thomas, Paul E; King, Christopher

2004-06-01

Two UDP-glucuronosyltransferases (UGT2B9(*)2 and UGT2B33) have been isolated from female rhesus monkey liver. Microsomal preparations of the cell lines expressing the UGTs catalyzed the glucuronidation of the general substrate 7-hydroxy-4-(trifluoromethyl)coumarin in addition to selected estrogens (beta-estradiol and estriol) and opioids (morphine, naloxone, and naltrexone). UGT2B9(*)2 displayed highest efficiency for beta-estradiol-17-glucuronide production and did not catalyze the glucuronidation of naltrexone. UGT2B33 displayed highest efficiency for estriol and did not catalyze the glucuronidation of beta-estradiol. UGT2B9(*)2 was found also to catalyze the glucuronidation of 4-hydroxyestrone, 16-epiestriol, and hyodeoxycholic acid, while UGT2B33 was capable of conjugating 4-hydroxyestrone, androsterone, diclofenac, and hyodeoxycholic acid. Three glucocorticoids (cortisone, cortisol, and corticosterone) were not substrates for glucuronidation by liver or kidney microsomes or any expressed UGTs. Our current data suggest the use of beta-estradiol-3-glucuronidation, beta-estradiol-17-glucuronidation, and estriol-17-glucuronidation to assay UGT1A01, UGT2B9(*)2, and UGT2B33 activity in rhesus liver microsomes, respectively.

Evaluation of monkey intraocular pressure by rebound tonometer

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Yu, Wenhan; Cao, Guiqun; Qiu, Jinghua; Ma, Jia; Li, Ni; Yu, Man; Yan, Naihong; Chen, Lei; Pang, Iok-Hou

2009-01-01

Purpose To evaluate the usefulness of the TonoVet™ rebound tonometer in measuring intraocular pressure (IOP) of monkeys. Methods The accuracy of the TonoVet™ rebound tonometer was determined in cannulated eyes of anesthetized rhesus monkeys where IOP was controlled by adjusting the height of a connected perfusate reservoir. To assess the applicability of the equipment through in vivo studies, the diurnal fluctuation of IOP and effects of IOP-lowering compounds were evaluated in monkeys. Results IOP readings generated by the TonoVet™ tonometer correlated very well with the actual pressure in the cannulated monkey eye. The linear correlation had a slope of 0.922±0.014 (mean±SEM, n=4), a y-intercept of 3.04±0.61, and a correlation coefficient of r2=0.97. Using this method, diurnal IOP fluctuation of the rhesus monkey was demonstrated. The tonometer was also able to detect IOP changes induced by pharmacologically active compounds. A single topical ocular instillation (15 μg) of the rho kinase inhibitor, H1152, produced a 5–6 mmHg reduction (pmonkey eye. PMID:19898690

Development of a cerebrospinal fluid lateral reservoir model in rhesus monkeys (Macaca mulatta).

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Lester McCully, Cynthia M; Bacher, John; MacAllister, Rhonda P; Steffen-Smith, Emilie A; Saleem, Kadharbatcha; Thomas, Marvin L; Cruz, Rafael; Warren, Katherine E

2015-02-01

Rapid, serial, and humane collection of cerebrospinal fluid (CSF) in nonhuman primates (NHP) is an essential element of numerous research studies and is currently accomplished via two different models. The CSF reservoir model (FR) combines a catheter in the 4th ventricle with a flexible silastic reservoir to permit circulating CSF flow. The CSF lateral port model (LP) consists of a lateral ventricular catheter and an IV port that provides static access to CSF and volume restrictions on sample collection. The FR model is associated with an intensive, prolonged recovery and frequent postsurgical hydrocephalus and nonpatency, whereas the LP model is associated with an easier recovery. To maximize the advantages of both systems, we developed the CSF lateral reservoir model (LR), which combines the beneficial features of the 2 previous models but avoids their limitations by using a reservoir for circulating CSF flow combined with catheter placement in the lateral ventricle. Nine adult male rhesus monkeys were utilized in this study. Pre-surgical MRI was performed to determine the coordinates of the lateral ventricle and location of choroid plexus (CP). The coordinates were determined to avoid the CP and major blood vessels. The predetermined coordinates were 100% accurate, according to MRI validation. The LR system functioned successfully in 67% of cases for 221 d, and 44% remain functional at 426 to 510 d postoperatively. Compared with established models, our LR model markedly reduced postoperative complications and recovery time. Development of the LR model was successful in rhesus macaques and is a useful alternative to the FR and LP methods of CSF collection from nonhuman primates.

Virulence of invasive Salmonella Typhimurium ST313 in animal models of infection.

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Girish Ramachandran

2017-08-01

Full Text Available Salmonella Typhimurium sequence type (ST 313 produces septicemia in infants in sub-Saharan Africa. Although there are known genetic and phenotypic differences between ST313 strains and gastroenteritis-associated ST19 strains, conflicting data about the in vivo virulence of ST313 strains have been reported. To resolve these differences, we tested clinical Salmonella Typhimurium ST313 and ST19 strains in murine and rhesus macaque infection models. The 50% lethal dose (LD50 was determined for three Salmonella Typhimurium ST19 and ST313 strains in mice. For dissemination studies, bacterial burden in organs was determined at various time-points post-challenge. Indian rhesus macaques were infected with one ST19 and one ST313 strain. Animals were monitored for clinical signs and bacterial burden and pathology were determined. The LD50 values for ST19 and ST313 infected mice were not significantly different. However, ST313-infected BALB/c mice had significantly higher bacterial numbers in blood at 24 h than ST19-infected mice. ST19-infected rhesus macaques exhibited moderate-to-severe diarrhea while ST313-infected monkeys showed no-to-mild diarrhea. ST19-infected monkeys had higher bacterial burden and increased inflammation in tissues. Our data suggest that Salmonella Typhimurium ST313 invasiveness may be investigated using mice. The non-human primate results are consistent with clinical data, suggesting that ST313 strains do not cause diarrhea.

Virulence of invasive Salmonella Typhimurium ST313 in animal models of infection.

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Ramachandran, Girish; Panda, Aruna; Higginson, Ellen E; Ateh, Eugene; Lipsky, Michael M; Sen, Sunil; Matson, Courtney A; Permala-Booth, Jasnehta; DeTolla, Louis J; Tennant, Sharon M

2017-08-01

Salmonella Typhimurium sequence type (ST) 313 produces septicemia in infants in sub-Saharan Africa. Although there are known genetic and phenotypic differences between ST313 strains and gastroenteritis-associated ST19 strains, conflicting data about the in vivo virulence of ST313 strains have been reported. To resolve these differences, we tested clinical Salmonella Typhimurium ST313 and ST19 strains in murine and rhesus macaque infection models. The 50% lethal dose (LD50) was determined for three Salmonella Typhimurium ST19 and ST313 strains in mice. For dissemination studies, bacterial burden in organs was determined at various time-points post-challenge. Indian rhesus macaques were infected with one ST19 and one ST313 strain. Animals were monitored for clinical signs and bacterial burden and pathology were determined. The LD50 values for ST19 and ST313 infected mice were not significantly different. However, ST313-infected BALB/c mice had significantly higher bacterial numbers in blood at 24 h than ST19-infected mice. ST19-infected rhesus macaques exhibited moderate-to-severe diarrhea while ST313-infected monkeys showed no-to-mild diarrhea. ST19-infected monkeys had higher bacterial burden and increased inflammation in tissues. Our data suggest that Salmonella Typhimurium ST313 invasiveness may be investigated using mice. The non-human primate results are consistent with clinical data, suggesting that ST313 strains do not cause diarrhea.

Effects of continuous hyperfractionated accelerated and conventionally fractionated radiotherapy on the parotid and submandibular salivary glands of rhesus monkeys

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Price, R.E.; Ang, K.K.; Stephens, L.C.; Peters, L.J.

1995-01-01

Radiotherapy is a major treatment modality for head and neck cancer. It is often not possible to exclude the salivary glands from the treatment fields. The unique susceptibility of the serous cells of the salivary glands to irradiation often results in xerostomia with ensuing secondary complications and discomfort to the patients. Recent reports have suggested that continuous hyperfractionated accelerated radiotherapy (CHART) can lead to considerably less reduction in salivary flow of the parotid salivary gland than conventional radiotherapy. This study was undertaken to assess histologic changes of salivary glands induced by CHART and conventional radiation fractionation schedules. The parotid and submandibular salivary glands of adult rhesus monkeys were irradiated with cobalt-60 γ radiation at 50 Gy/20 fractions/4 weeks, 55 Gy/25 fractions/5 weeks, or 54 Gy/36 fractions/12 days (CHART). Salivary tissues were harvested at 16 weeks following irradiation and evaluated histopathologically. Microscopically, the glands receiving 50 Gy, 55 Gy, or CHART were virtually indistinguishable. There was severe atrophy and fibrosis of all glands. Quantitative analysis revealed that 50 Gy, 55 Gy, and CHART induced a reduction of serous acini in parotid glands by 86.4%, 84.8%, and 88.8%, respectively. In submandibular glands, serous acini were reduced by 99.4%, 99.0%, and 100%, respectively. The corresponding reduction in mucous acini were 98.4%, 98.4%, and 99.2%, respectively. These histopathologic and quantitative morphologic studies show that the magnitude of serous gland atrophy in the parotid and submandibular salivary glands of rhesus monkeys was similar at 16 weeks after receiving 50 Gy in 20 fractions, 55 Gy in 25 fractions, or CHART

Blood to brain iron uptake in one Rhesus monkey using [Fe-52]-citrate and positron emission tomography (PET): influence of haloperidol

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Leenders, K L [Paul Scherrer Inst., Villigen (Switzerland); [Neurology Dept., Univ. Hospital, Zuerich (Switzerland); Antonini, A; Schwarzbach, R; Smith-Jones, P; Reist, H [Paul Scherrer Inst., Villigen (Switzerland); Youdim, M [Pharmacology Dept., Technion, Haifa (Israel); Henn, V [Neurology Dept., Univ. Hospital, Zuerich (Switzerland)

1994-12-31

Iron is highly concentrated in the basal ganglia of the brain. The involvement of cerebral iron and its handling systems in neurodegenerative brain diseases like Parkinson`s disease and tardive dyskinesia is currently under close investigation. There is evidence from animal studies that neuroleptics can increase iron uptake into brain. This effect appeared to be due to alteration of blood-brain barrier transport by the neuroleptics, particularly chlorpromazine and haloperidol, but not clozapine. We have investigated one Rhesus monkey using positron emission tomography (PET) and [Fe-52]-citrate before and during haloperidol administration. After drug withdrawal during a period of 1.5 year the investigation procedure was repeated. The results show that in the investigated monkey haloperidol induces a reversible marked increase of iron transport across the blood brain barrier concomitant with a large increase in elimination rate of the tracer from the blood. (author).

Blood to brain iron uptake in one Rhesus monkey using [Fe-52]-citrate and positron emission tomography (PET): influence of haloperidol

International Nuclear Information System (INIS)

Leenders, K.L.; Antonini, A.; Schwarzbach, R.; Smith-Jones, P.; Reist, H.; Youdim, M.; Henn, V.

1994-01-01

Iron is highly concentrated in the basal ganglia of the brain. The involvement of cerebral iron and its handling systems in neurodegenerative brain diseases like Parkinson's disease and tardive dyskinesia is currently under close investigation. There is evidence from animal studies that neuroleptics can increase iron uptake into brain. This effect appeared to be due to alteration of blood-brain barrier transport by the neuroleptics, particularly chlorpromazine and haloperidol, but not clozapine. We have investigated one Rhesus monkey using positron emission tomography (PET) and [Fe-52]-citrate before and during haloperidol administration. After drug withdrawal during a period of 1.5 year the investigation procedure was repeated. The results show that in the investigated monkey haloperidol induces a reversible marked increase of iron transport across the blood brain barrier concomitant with a large increase in elimination rate of the tracer from the blood. (author)

Limited ability of humoral immune responses in control of viremia during infection with SIVsmmD215 strain

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Ribiero, Ruy M [Los Alamos National Laboratory

2009-01-01

To investigate the impact of humoral immunity on SIV replication, 11 rhesus macaques (RMs) were inoculated with the neutralization-sensitive strain SIVsmmD215. Seven RMs were treated every three weeks, with 50 mglkg of an anti-CD20 antibody (Rituxan, gift from Genentech) starting from day -7 p.i., as follows: four RMs were treated for two months, and three were treated for five months. The remaining four RMs were used as controls. Three RMs were completely depleted of CD20 cells. Four RMs only partially depleted CD20 cells in the LNs and intestine. The efficacy of tissue CD20 depletion predicted the ablation of antibody production, with SIVsmm seroconversion being delayed in the animals with complete tissue CD20 depletion, and neutralizing antibody production being significantly delayed and at low levels in all CD20-depleted RMs. There was no significant difference in acute or chronic VLs between CD20-depleted RMs and control monkeys, with a tendency for lower set-point VLs in CD20-depleted RMs. At 6 weeks p.i., cellular immune responses were significantly stronger in CD20 depleted RMs than in controls. After two years p.i., there was no significant difference in survival between CD20-depleted and control RMs. We concluded that CD20 depletion plays no significant role in the control of SIV replication or disease progression in SIVsmmD215-infected RMs.

HIV vaccine research and discovery in the nonhuman primates model: a unified theory in acquisition prevention and control of SIV infection.

Science.gov (United States)

Lynch, Rebecca M; Yamamoto, Takuya; McDermott, Adrian B

2013-07-01

Here we highlight the latest advances in HIV vaccine concepts that will expand our knowledge on how to elicit effective acquisition-prevention and/or control of simian immunodeficiency virus (SIV) replication in the nonhuman primate (NHP) model. In the context of the promising analyses from the RV144 Thai Trial and the effective control of SIV replication exerted by rhCMV-(SIV) elicited EM CD8 T cells, the HIV field has recently shifted toward vaccine concepts that combine protection from acquisition with effective control of SIV replication. Current studies in the NHP model have demonstrated the efficacy of HIV-neutralizing antibodies via passive transfer, the potential importance of the CD4 Tfh subset, the ability to effectively model the RV144 vaccine trial and the capacity of an Ad26 prime and modified vaccinia Ankara virus boost to elicit Env-specific antibody and cellular responses that both limit acquisition and control heterologous SIVmac251 challenge. The latest work in the NHP model suggests that the next generation HIV-1 vaccines should aim to provoke a comprehensive adaptive immune response for both prevention of SIV acquisition as well as control of replication in breakthrough infection.

Sub-chronic inhalation of high concentrations of manganese sulfate induces lower airway pathology in rhesus monkeys

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Wong Brian A

2005-10-01

Full Text Available Abstract Background Neurotoxicity and pulmonary dysfunction are well-recognized problems associated with prolonged human exposure to high concentrations of airborne manganese. Surprisingly, histological characterization of pulmonary responses induced by manganese remains incomplete. The primary objective of this study was to characterize histologic changes in the monkey respiratory tract following manganese inhalation. Methods Subchronic (6 hr/day, 5 days/week inhalation exposure of young male rhesus monkeys to manganese sulfate was performed. One cohort of monkeys (n = 4–6 animals/exposure concentration was exposed to air or manganese sulfate at 0.06, 0.3, or 1.5 mg Mn/m3 for 65 exposure days. Another eight monkeys were exposed to manganese sulfate at 1.5 mg Mn/m3 for 65 exposure days and held for 45 or 90 days before evaluation. A second cohort (n = 4 monkeys per time point was exposed to manganese sulfate at 1.5 mg Mn/m3 and evaluated after 15 or 33 exposure days. Evaluations included measurement of lung manganese concentrations and evaluation of respiratory histologic changes. Tissue manganese concentrations were compared for the exposure and control groups by tests for homogeneity of variance, analysis of variance, followed by Dunnett's multiple comparison. Histopathological findings were evaluated using a Pearson's Chi-Square test. Results Animals exposed to manganese sulfate at ≥0.3 mg Mn/m3 for 65 days had increased lung manganese concentrations. Exposure to manganese sulfate at 1.5 mg Mn/m3 for ≥15 exposure days resulted in increased lung manganese concentrations, mild subacute bronchiolitis, alveolar duct inflammation, and proliferation of bronchus-associated lymphoid tissue. Bronchiolitis and alveolar duct inflammatory changes were absent 45 days post-exposure, suggesting that these lesions are reversible upon cessation of subchronic high-dose manganese exposure. Conclusion High-dose subchronic manganese sulfate inhalation is

An "escape clock" for estimating the turnover of SIV DNA in resting CD4⁺ T cells.

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Jeanette Reece

Full Text Available Persistence of HIV DNA presents a major barrier to the complete control of HIV infection under current therapies. Most studies suggest that cells with latently integrated HIV decay very slowly under therapy. However, it is much more difficult to study the turnover and persistence of HIV DNA during active infection. We have developed an "escape clock" approach for measuring the turnover of HIV DNA in resting CD4+ T cells. This approach studies the replacement of wild-type (WT SIV DNA present in early infection by CTL escape mutant (EM strains during later infection. Using a strain-specific real time PCR assay, we quantified the relative amounts of WT and EM strains in plasma SIV RNA and cellular SIV DNA. Thus we can track the formation and turnover of SIV DNA in sorted resting CD4+ T cells. We studied serial plasma and PBMC samples from 20 SIV-infected Mane-A*10 positive pigtail macaques that have a signature Gag CTL escape mutation. In animals with low viral load, WT virus laid down early in infection is extremely stable, and the decay of this WT species is very slow, consistent with findings in subjects on anti-retroviral medications. However, during active, high level infection, most SIV DNA in resting cells was turning over rapidly, suggesting a large pool of short-lived DNA produced by recent infection events. Our results suggest that, in order to reduce the formation of a stable population of SIV DNA, it will be important either to intervene very early or intervene during active replication.

Rectal HSV-2 Infection May Increase Rectal SIV Acquisition Even in the Context of SIVΔnef Vaccination.

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Natalia Guerra-Pérez

Full Text Available Prevalent HSV-2 infection increases the risk of HIV acquisition both in men and women even in asymptomatic subjects. Understanding the impact of HSV-2 on the mucosal microenvironment may help to identify determinants of susceptibility to HIV. Vaginal HSV-2 infection increases the frequency of cells highly susceptible to HIV in the vaginal tissue of women and macaques and this correlates with increased susceptibility to vaginal SHIV infection in macaques. However, the effect of rectal HSV-2 infection on HIV acquisition remains understudied. We developed a model of rectal HSV-2 infection in macaques in combination with rectal SIVmac239Δnef (SIVΔnef vaccination and our results suggest that rectal HSV-2 infection may increase the susceptibility of macaques to rectal SIVmac239 wild-type (wt infection even in SIVΔnef-infected animals. Rectal SIVΔnef infection/vaccination protected 7 out of 7 SIVΔnef-infected macaques from SIVmac239wt rectal infection (vs 12 out of 16 SIVΔnef-negative macaques, while 1 out of 3 animals co-infected with SIVΔnef and HSV-2 acquired SIVmac239wt infection. HSV-2/SIVmac239wt co-infected animals had increased concentrations of inflammatory factors in their plasma and rectal fluids and a tendency toward higher acute SIVmac239wt plasma viral load. However, they had higher blood CD4 counts and reduced depletion of CCR5+ CD4+ T cells compared to SIVmac239wt-only infected animals. Thus, rectal HSV-2 infection generates a pro-inflammatory environment that may increase susceptibility to rectal SIV infection and may impact immunological and virological parameters during acute SIV infection. Studies with larger number of animals are needed to confirm these findings.

Anti-retroviral therapy fails to restore the severe Th-17: Tc-17 imbalance observed in peripheral blood during simian immunodeficiency virus infection.

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Kader, M; Bixler, S; Piatak, M; Lifson, J; Mattapallil, J J

2009-10-01

Human immuno deficiency virus and simian immunodeficiency virus infections are characterized by a severe loss of Th-17 cells (IL-17(+)CD4(+) T cells) that has been associated with disease progression and systemic dissemination of bacterial infections. Anti-retroviral therapy (ART) has led to repopulation of CD4(+) T cells in peripheral tissues with little sustainable repopulation in mucosal tissues. Given the central importance of Th-17 cells in mucosal homeostasis, it is not known if the failure of ART to permanently repopulate mucosal tissues is associated with a failure to restore Th-17 cells that are lost during infection. Dynamics of alpha4(+)beta7(hi) CD4(+) T cells in peripheral blood of SIV infected rhesus macaques were evaluated and compared to animals that were treated with ART. The frequency of Th-17 and Tc-17 cells was determined following infection and after therapy. Relative expression of IL-21, IL-23, and TGFbeta was determined using Taqman PCR. Treatment of SIV infected rhesus macaques with anti-retroviral therapy was associated with a substantial repopulation of mucosal homing alpha4(+)beta7(hi)CD4(+) T cells in peripheral blood. This repopulation, however, was not accompanied by a restoration of Th-17 responses. Interestingly, SIV infection was associated with an increase in Tc-17 responses (IL-17(+)CD8(+) T cells) suggesting to a skewing in the ratio of Th-17: Tc-17 cells from a predominantly Th-17 phenotype to a predominantly Tc-17 phenotype. Surprisingly, Tc-17 responses remained high during the course of therapy suggesting that ART failed to correct the imbalance in Th-17 : Tc-17 responses induced following SIV infection. ART was associated with substantial repopulation of alpha4(+)beta7(hi) CD4(+) T cells in peripheral blood with little or no rebound of Th-17 cells. On the other hand, repopulation of alpha4(+)beta7(hi) CD4(+) T cells was accompanied by persistence of high levels of Tc-17 cells in peripheral blood. The dysregulation of Th-17

Host immune responses to a viral immune modulating protein: immunogenicity of viral interleukin-10 in rhesus cytomegalovirus-infected rhesus macaques.

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Meghan K Eberhardt

Full Text Available Considerable evidence has accumulated that multiple viruses, bacteria, and protozoa manipulate interleukin-10 (IL-10-mediated signaling through the IL-10 receptor (IL-10R in ways that could enable establishment of a persistent microbial infection. This suggests that inhibition of pathogen targeting of IL-10/IL-10R signaling could prevent microbial persistence. Human cytomegalovirus (HCMV and rhesus cytomegalovirus (RhCMV express a viral interleukin-10 (cmvIL-10 and rhcmvIL-10, respectively with comparable immune modulating properties in vitro to that of their host's cellular IL-10 (cIL-10. A prior study noted that rhcmvIL-10 alters innate and adaptive immunity to RhCMV in vivo, consistent with a central role for rhcmvIL-10 during acute virus-host interactions. Since cmvIL-10 and rhcmvIL-10 are extremely divergent from the cIL-10 of their respective hosts, vaccine-mediated neutralization of their function could inhibit establishment of viral persistence without inhibition of cIL-10.As a prelude to evaluating cmvIL-10-based vaccines in humans, the rhesus macaque model of HCMV was used to interrogate peripheral and mucosal immune responses to rhcmvIL-10 in RhCMV-infected animals. ELISA were used to detect rhcmvIL-10-binding antibodies in plasma and saliva, and an IL-12-based bioassay was used to quantify plasma antibodies that neutralized rhcmvIL-10 function. rhcmvIL-10 is highly immunogenic during RhCMV infection, stimulating high avidity rhcmvIL-10-binding antibodies in the plasma of all infected animals. Most infected animals also exhibited plasma antibodies that partially neutralized rhcmvIL-10 function but did not cross-neutralize the function of rhesus cIL-10. Notably, minimally detectable rhcmvIL-10-binding antibodies were detected in saliva.This study demonstrates that rhcmvIL-10, as a surrogate for cmvIL-10, is a viable vaccine candidate because (1 it is highly immunogenic during natural RhCMV infection, and (2 neutralizing antibodies to

Elevated Basal Pre-infection CXCL10 in Plasma and in the Small Intestine after Infection Are Associated with More Rapid HIV/SIV Disease Onset.

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Mickaël J Ploquin

2016-08-01

Full Text Available Elevated blood CXCL10/IP-10 levels during primary HIV-1 infection (PHI were described as an independent marker of rapid disease onset, more robust than peak viremia or CD4 cell nadir. IP-10 enhances the recruitment of CXCR3+ cells, which include major HIV-target cells, raising the question if it promotes the establishment of viral reservoirs. We analyzed data from four cohorts of HIV+ patients, allowing us to study IP-10 levels before infection (Amsterdam cohort, as well as during controlled and uncontrolled viremia (ANRS cohorts. We also addressed IP-10 expression levels with regards to lymphoid tissues (LT and blood viral reservoirs in patients and non-human primates. Pre-existing elevated IP-10 levels but not sCD63 associated with rapid CD4 T-cell loss upon HIV-1 infection. During PHI, IP-10 levels and to a lesser level IL-18 correlated with cell-associated HIV DNA, while 26 other inflammatory soluble markers did not. IP-10 levels tended to differ between HIV controllers with detectable and undetectable viremia. IP-10 was increased in SIV-exposed aviremic macaques with detectable SIV DNA in tissues. IP-10 mRNA was produced at higher levels in the small intestine than in colon or rectum. Jejunal IP-10+ cells corresponded to numerous small and round CD68neg cells as well as to macrophages. Blood IP-10 response negatively correlated with RORC (Th17 marker gene expression in the small intestine. CXCR3 expression was higher on memory CD4+ T cells than any other immune cells. CD4 T cells from chronically infected animals expressed extremely high levels of intra-cellular CXCR3 suggesting internalization after ligand recognition. Elevated systemic IP-10 levels before infection associated with rapid disease progression. Systemic IP-10 during PHI correlated with HIV DNA. IP-10 production was regionalized in the intestine during early SIV infection and CD68+ and CD68neg haematopoietic cells in the small intestine appeared to be the major source of IP-10.

Attenuation of Pathogenic Immune Responses during Infection with Human and Simian Immunodeficiency Virus (HIV/SIV) by the Tetracycline Derivative Minocycline

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Drewes, Julia L.; Szeto, Gregory L.; Engle, Elizabeth L.; Liao, Zhaohao; Shearer, Gene M.; Zink, M. Christine; Graham, David R.

2014-01-01

HIV immune pathogenesis is postulated to involve two major mechanisms: 1) chronic innate immune responses that drive T cell activation and apoptosis and 2) induction of immune regulators that suppress T cell function and proliferation. Both arms are elevated chronically in lymphoid tissues of non-natural hosts, which ultimately develop AIDS. However, these mechanisms are not elevated chronically in natural hosts of SIV infection that avert immune pathogenesis despite similarly high viral loads. In this study we investigated whether minocycline could modulate these pathogenic antiviral responses in non-natural hosts of HIV and SIV. We found that minocycline attenuated in vitro induction of type I interferon (IFN) and the IFN-stimulated genes indoleamine 2,3-dioxygenase (IDO1) and TNF-related apoptosis inducing ligand (TRAIL) in human plasmacytoid dendritic cells and PBMCs exposed to aldrithiol-2 inactivated HIV or infectious influenza virus. Activation-induced TRAIL and expression of cytotoxic T-lymphocyte antigen 4 (CTLA-4) in isolated CD4+ T cells were also reduced by minocycline. Translation of these in vitro findings to in vivo effects, however, were mixed as minocycline significantly reduced markers of activation and activation-induced cell death (CD25, Fas, caspase-3) but did not affect expression of IFNβ or the IFN-stimulated genes IDO1, FasL, or Mx in the spleens of chronically SIV-infected pigtailed macaques. TRAIL expression, reflecting the mixed effects of minocycline on activation and type I IFN stimuli, was reduced by half, but this change was not significant. These results show that minocycline administered after infection may protect against aspects of activation-induced cell death during HIV/SIV immune disease, but that in vitro effects of minocycline on type I IFN responses are not recapitulated in a rapid progressor model in vivo. PMID:24732038

Steroid metabolism by monkey and human spermatozoa

International Nuclear Information System (INIS)

Rajalakshmi, M.; Sehgal, A.; Pruthi, J.S.; Anand-Kumar, T.C.

1983-01-01

Freshly ejaculated spermatozoa from monkey and human were washed and incubated with tritium labelled androgens or estradiol to study the pattern of spermatozoa steroid metabolism. When equal concentrations of steroid substrates were used for incubation, monkey and human spermatozoa showed very similar pattern of steroid conversion. Spermatozoa from both species converted testosterone mainly to androstenedione, but reverse conversion of androstenedione to testosterone was negligible. Estradiol-17 beta was converted mainly to estrone. The close similarity between the spermatozoa of monkey and men in their steroid metabolic pattern indicates that the rhesus monkey could be an useful animal model to study the effect of drugs on the metabolic pattern of human spermatozoa

Development of a high-titer retrovirus producer cell line capable of gene transfer into rhesus monkey hematopoietic stem cells

International Nuclear Information System (INIS)

Bodine, D.M.; McDonagh, K.T.; Brandt, S.J.; Ney, P.A.; Agricola, B.; Byrne, E.; Nienhuis, A.W.

1990-01-01

Retroviral-mediated gene transfer into primitive hematopoietic cells has been difficult to achieve in large-animal models. The authors have developed an amphotropic producer clone that generates >10 10 recombinant retroviral particles (colony-forming units) per ml of culture medium. Autologous rhesus monkey bone marrow cells were cocultured with either high or low titer producer clones for 4-6 days and reinfused into sublethally irradiated animals. The proviral genome was detected in blood and bone-marrow cells from all three animals reconstituted with cells cocultured with the high-titer producer cells. In contrast, three animals reconstituted with bone marrow cocultured with the low-titer producer clone exhibited no evidence of gene transfer

Similarities in the immunoglobulin response and VH gene usage in rhesus monkeys and humans exposed to porcine hepatocytes

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Borie Dominic C

2006-03-01

Full Text Available Abstract Background The use of porcine cells and organs as a source of xenografts for human patients would vastly increase the donor pool; however, both humans and Old World primates vigorously reject pig tissues due to xenoantibodies that react with the polysaccharide galactose α (1,3 galactose (αGal present on the surface of many porcine cells. We previously examined the xenoantibody response in patients exposed to porcine hepatocytes via treatment(s with bioartficial liver devices (BALs, composed of porcine cells in a support matrix. We determined that xenoantibodies in BAL-treated patients are predominantly directed at porcine αGal carbohydrate epitopes, and are encoded by a small number of germline heavy chain variable region (VH immunoglobulin genes. The studies described in this manuscript were designed to identify whether the xenoantibody responses and the IgVH genes encoding antibodies to porcine hepatocytes in non-human primates used as preclinical models are similar to those in humans. Adult non-immunosuppressed rhesus monkeys (Macaca mulatta were injected intra-portally with porcine hepatocytes or heterotopically transplanted with a porcine liver lobe. Peripheral blood leukocytes and serum were obtained prior to and at multiple time points after exposure, and the immune response was characterized, using ELISA to evaluate the levels and specificities of circulating xenoantibodies, and the production of cDNA libraries to determine the genes used by B cells to encode those antibodies. Results Xenoantibodies produced following exposure to isolated hepatocytes and solid organ liver grafts were predominantly encoded by genes in the VH3 family, with a minor contribution from the VH4 family. Immunoglobulin heavy-chain gene (VH cDNA library screening and gene sequencing of IgM libraries identified the genes as most closely-related to the IGHV3-11 and IGHV4-59 germline progenitors. One of the genes most similar to IGHV3-11, VH3-11cyno, has

Control of Working Memory in Rhesus Monkeys (Macaca mulatta)

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Tu, Hsiao-Wei; Hampton, Robert R.

2014-01-01

Cognitive control is critical for efficiently using the limited resources in working memory. It is well established that humans use rehearsal to increase the probability of remembering needed information, but little is known in nonhumans, with some studies reporting the absence of active control and others subject to alternative explanations. We trained monkeys in a visual matching-to-sample paradigm with a post-sample memory cue. Monkeys either saw a remember cue that predicted the occurrence of a matching test that required memory for the sample, or a forget cue that predicted a discrimination test that did not require memory of the sample. Infrequent probe trials on which monkeys were given tests of the type not cued on that trial were used to assess whether memory was under cognitive control. Our procedures controlled for reward expectation and for the surprising nature of the probes. Monkeys matched less accurately after forget cues, while discrimination accuracy was equivalent in the two cue conditions. We also tested monkeys with lists of two consecutive sample images that shared the same cue. Again, memory for expected memory tests was superior to that on unexpected tests. Together these results show that monkeys cognitively control their working memory. PMID:25436219

Short-term testosterone manipulations do not affect cognition or motor function but differentially modulate emotions in young and older male rhesus monkeys.

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Kelly, Brian; Maguire-Herring, Vanessa; Rose, Christian M; Gore, Heather E; Ferrigno, Stephen; Novak, Melinda A; Lacreuse, Agnès

2014-11-01

Human aging is characterized by declines in cognition and fine motor function as well as improved emotional regulation. In men, declining levels of testosterone (T) with age have been implicated in the development of these age-related changes. However, studies examining the effects of T replacement on cognition, emotion and fine motor function in older men have not provided consistent results. Rhesus monkeys (Macaca mulatta) are excellent models for human cognitive aging and may provide novel insights on this issue. We tested 10 aged intact male rhesus monkeys (mean age=19, range 15-25) on a battery of cognitive, motor and emotional tasks at baseline and under low or high T experimental conditions. Their performance was compared to that of 6 young males previously tested in the same paradigm (Lacreuse et al., 2009; Lacreuse et al., 2010). Following a 4-week baseline testing period, monkeys were treated with a gonadotropin releasing hormone agonist (Depot Lupron, 200 μg/kg) to suppress endogenous T and were tested on the task battery under a 4-week high T condition (injection of Lupron+T enanthate, 20 mg/kg, n=8) or 4-week low T condition (injection of Lupron+oil vehicle, n=8) before crossing over to the opposite treatment. The cognitive tasks consisted of the Delayed Non-Matching-to-Sample (DNMS), the Delayed Response (DR), and the Delayed Recognition Span Test (spatial-DRST). The emotional tasks included an object Approach-Avoidance task and a task in which monkeys were played videos of unfamiliar conspecifics in different emotional context (Social Playbacks). The fine motor task was the Lifesaver task that required monkeys to remove a Lifesaver candy from rods of different complexity. T manipulations did not significantly affect visual recognition memory, working memory, reference memory or fine motor function at any age. In the Approach-Avoidance task, older monkeys, but not younger monkeys, spent more time in proximity of novel objects in the high T condition

Natural host genetic resistance to lentiviral CNS disease: a neuroprotective MHC class I allele in SIV-infected macaques.

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Joseph L Mankowski

Full Text Available Human immunodeficiency virus (HIV infection frequently causes neurologic disease even with anti-retroviral treatment. Although associations between MHC class I alleles and acquired immunodeficiency syndrome (AIDS have been reported, the role MHC class I alleles play in restricting development of HIV-induced organ-specific diseases, including neurologic disease, has not been characterized. This study examined the relationship between expression of the MHC class I allele Mane-A*10 and development of lentiviral-induced central nervous system (CNS disease using a well-characterized simian immunodeficiency (SIV/pigtailed macaque model. The risk of developing CNS disease (SIV encephalitis was 2.5 times higher for animals that did not express the MHC class I allele Mane-A*10 (P = 0.002; RR = 2.5. Animals expressing the Mane-A*10 allele had significantly lower amounts of activated macrophages, SIV RNA, and neuronal dysfunction in the CNS than Mane-A*10 negative animals (P<0.001. Mane-A*10 positive animals with the highest CNS viral burdens contained SIV gag escape mutants at the Mane-A*10-restricted KP9 epitope in the CNS whereas wild type KP9 sequences dominated in the brain of Mane-A*10 negative animals with comparable CNS viral burdens. These concordant findings demonstrate that particular MHC class I alleles play major neuroprotective roles in lentiviral-induced CNS disease.

MRI Overestimates Excitotoxic Amygdala Lesion Damage in Rhesus Monkeys

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Benjamin M. Basile

2017-06-01

Full Text Available Selective, fiber-sparing excitotoxic lesions are a state-of-the-art tool for determining the causal contributions of different brain areas to behavior. For nonhuman primates especially, it is advantageous to keep subjects with high-quality lesions alive and contributing to science for many years. However, this requires the ability to estimate lesion extent accurately. Previous research has shown that in vivo T2-weighted magnetic resonance imaging (MRI accurately estimates damage following selective ibotenic acid lesions of the hippocampus. Here, we show that the same does not apply to lesions of the amygdala. Across 19 hemispheres from 13 rhesus monkeys, MRI assessment consistently overestimated amygdala damage as assessed by microscopic examination of Nissl-stained histological material. Two outliers suggested a linear relation for lower damage levels, and values of unintended amygdala damage from a previous study fell directly on that regression line, demonstrating that T2 hypersignal accurately predicts damage levels below 50%. For unintended damage, MRI estimates correlated with histological assessment for entorhinal cortex, perirhinal cortex and hippocampus, though MRI significantly overestimated the extent of that damage in all structures. Nevertheless, ibotenic acid injections routinely produced extensive intentional amygdala damage with minimal unintended damage to surrounding structures, validating the general success of the technique. The field will benefit from more research into in vivo lesion assessment techniques, and additional evaluation of the accuracy of MRI assessment in different brain areas. For now, in vivo MRI assessment of ibotenic acid lesions of the amygdala can be used to confirm successful injections, but MRI estimates of lesion extent should be interpreted with caution.

Intraoperative contrast-enhanced ultrasonography for microcirculatory evaluation in rhesus monkey with spinal cord injury.

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Huang, Lin; Chen, Keng; Chen, Fu-Chao; Shen, Hui-Yong; Ye, Ji-Chao; Cai, Zhao-Peng; Lin, Xi

2017-06-20

This study tried to quantify spinal cord perfusion by using contrast-enhanced ultrasound (CEUS) in rhesus monkey models with acute spinal cord injury. Acute spinal cord perfusion after injury was detected by CEUS, coupling with conventional ultrasound (US) and Color Doppler US (CDFI). Time-intensity curves and perfusion parameters were obtained by autotracking contrast quantification (ACQ) software in the epicenter and adjacent regions of injury, respectively. Neurological and histological examinations were performed to confirm the severity of injury. US revealed spinal cords were hypoechoic and homogeneous, whereas dura maters, pia maters, and cerebral aqueducts were hyperechoic. After spinal cord contusion, the injured spinal cord was hyperechoic on US, and intramedullary vessels of adjacent region of injury were increased and dilated on CDFI. On CEUS hypoperfusion were found in the epicenter of injury, while hyperperfusion in its adjacent region. Quantitative analysis showed that peak intensity (PI) decreased in epicenters of injury but significantly increased in adjacent regions at all time points (p spinal cord injury in overall views and real-time.

Flow visualization through particle image velocimetry in realistic model of rhesus monkey's upper airway.

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Kim, Ji-Woong; Phuong, Nguyen Lu; Aramaki, Shin-Ichiro; Ito, Kazuhide

2018-05-01

Studies concerning inhalation toxicology and respiratory drug-delivery systems require biological testing involving experiments performed on animals. Particle image velocimetry (PIV) is an effective in vitro technique that reveals detailed inhalation flow patterns, thereby assisting analyses of inhalation exposure to various substances. A realistic model of a rhesus-monkey upper airway was developed to investigate flow patterns in its oral and nasal cavities through PIV experiments performed under steady-state constant inhalation conditions at various flow rates-4, 10, and 20 L/min. Flow rate of the fluid passing through the inlet into the trachea was measured to obtain characteristic flow mechanisms, and flow phenomena in the model were confirmed via characterized flow fields. It was observed that increase in flow rate leads to constant velocity profiles in upper and lower trachea regions. It is expected that the results of this study would contribute to future validation of studies aimed at developing in silico models, especially those involving computational fluid dynamic (CFD) analysis. Copyright © 2018 Elsevier B.V. All rights reserved.

Differences in behaviour and physiology between adult surrogate-reared and mother-reared Cynomolgous monkeys (Macaca fascicularis)

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Luijk, I.A.F. van; Timmermans, P.J.A.; Sweep, C.G.J.; Willems, J.; Vossen, J.M.H.

2000-01-01

Previous studies of the effects of rearing conditions on exploratory behaviour revealed that 80% of monkeys reared in peer groups with surrogate mothers developed neophobia, whereas only 15 % of mother-reared monkeys did. Young surrogate-reared and, especially, isolated rhesus monkeys are known to

Methamphetamine abuse affects gene expression in brain-derived microglia of SIV-infected macaques to enhance inflammation and promote virus targets

KAUST Repository

Najera, Julia A.

2016-04-23

Background Methamphetamine (Meth) abuse is a major health problem linked to the aggravation of HIV- associated complications, especially within the Central Nervous System (CNS). Within the CNS, Meth has the ability to modify the activity/function of innate immune cells and increase brain viral loads. Here, we examined changes in the gene expression profile of neuron-free microglial cell preparations isolated from the brain of macaques infected with the Simian Immunodeficiency Virus (SIV), a model of neuroAIDS, and exposed to Meth. We aimed to identify molecular patterns triggered by Meth that could explain the detection of higher brain viral loads and the development of a pro-inflammatory CNS environment in the brain of infected drug abusers. Results We found that Meth alone has a strong effect on the transcription of genes associated with immune pathways, particularly inflammation and chemotaxis. Systems analysis led to a strong correlation between Meth exposure and enhancement of molecules associated with chemokines and chemokine receptors, especially CXCR4 and CCR5, which function as co-receptors for viral entry. The increase in CCR5 expression was confirmed in the brain in correlation with increased brain viral load. Conclusions Meth enhances the availability of CCR5-expressing cells for SIV in the brain, in correlation with increased viral load. This suggests that Meth is an important factor in the susceptibility to the infection and to the aggravated CNS inflammatory pathology associated with SIV in macaques and HIV in humans.

[Explantation method of isolating a persistent tick-borne encephalitis virus from the organs of infected monkeys].

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Levina, L S; Pogodina, V V

1981-01-01

The method of explantation was used to examine 63 organs from M. rhesus monkeys 92-783 days after intracerebral and subcutaneous inoculation with the Vasilchenko, Aina/1448 and 41/65 strains of tick-borne encephalitis virus. The optimal time for examination of the explants by tests of the hemagglutinating, cytopathogenic activity of the virus and its pathogenicity for mice was found to be the 15th day of cultivation. A comparative study of the properties of 3 isolates obtained from explants of the spleen, liver and subcortical cerebral ganglia 202 and 307 days after inoculation of monkeys was carried out. The isolates differed from the parental TBE virus strains by their capacity to form small plaques in PEKV cell cultures (pig embryo kidney cells in versen medium).

Gastrointestinal decontamination in healthy and lethally irradiated monkeys

International Nuclear Information System (INIS)

Hendriks, W.D.H.

1980-01-01

In periods of extreme immunosuppression, infections which are often life-threatening, frequently occur. In an attempt to prevent such infections in lethally irradiated rhesus monkeys, the animals were subjected to strict reverse isolation prior to irradiation and administrated orally with nonabsorbable antibiotics in order to eliminate their microflora. The antibiotic combination was selected on the basis of a sensitivity test and was added to the liquid food supply. To rapidly achieve a high bactericidal concentration in the intestine, the same antibiotics were additionally given orally for 5 days. The microflora was reduced rapidly; within a few days sterile cultures were obtained. Particularly after discontinuation of the administration of the additional antibiotics were colonizations found. In contrast to colonizations persisting from the first day of treatment on, the first were rather easy to suppress. (Auth.)

Effects of 14-day treatment with the schedule III anorectic phendimetrazine on choice between cocaine and food in rhesus monkeys.

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Banks, Matthew L; Blough, Bruce E; Negus, S Stevens

2013-08-01

The clinical utility of monoamine releasers such as phenmetrazine or d-amphetamine as candidate agonist medications for cocaine dependence is hindered by their high abuse liability. Phendimetrazine is a clinically available schedule III anorectic that functions as a prodrug for phenmetrazine and thus may have lower abuse liability. This study determined the effects of continuous 14-day treatment with phendimetrazine on cocaine vs. food choice in rhesus monkeys (N=4). Responding was maintained under a concurrent schedule of food delivery (1-g pellets, fixed-ratio 100 schedule) and cocaine injections (0-0.1mg/kg/injection, fixed-ratio 10 schedule). Cocaine choice dose-effect curves were determined daily before and during 14-day periods of continuous intravenous treatment with saline or (+)-phendimetrazine (0.32-1.0mg/kg/h). Effects of 14-day treatment with (+)-phenmetrazine (0.1-0.32 mg/kg/h; N=5) and d-amphetamine (0.032-0.1mg/kg/h; N=6) were also examined for comparison. During saline treatment, food was primarily chosen during availability of low cocaine doses (0, 0.0032, and 0.01 mg/kg/injection), and cocaine was primarily chosen during availability of higher cocaine doses (0.032 and 0.1mg/kg/injection). Phendimetrazine initially decreased overall responding without significantly altering cocaine choice. Over the course of 14 days, tolerance developed to rate decreasing effects, and phendimetrazine dose-dependently decreased cocaine choice (significant at 0.032 mg/kg/injection cocaine). Phenmetrazine and d-amphetamine produced qualitatively similar effects. These results demonstrate that phendimetrazine can produce significant, though modest, reductions in cocaine choice in rhesus monkeys. Phendimetrazine may be especially suitable as a candidate medication for human studies because of its schedule III clinical availability. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Nuclear weapon testing and the monkey business

International Nuclear Information System (INIS)

Murthy, M.S.S.

1978-01-01

Reasons for India's total ban on the export of rhesus monkeys to U.S. have been explained. The major reason is that some of the animals were used in nuclear weapon related radiation experiments. This was a clear violation of a stricture in the agreement about supply of monkeys. The stricture prohibited the use of animals for research concerning military operations, including nuclear weapon testing. It is pleaded that a strict enforcement of strictures rather than a total ban on the export of monkeys would be better in the interest of advancement of knowledge in human medicine and disease control. (M.G.B.)

Methamphetamine abuse affects gene expression in brain-derived microglia of SIV-infected macaques to enhance inflammation and promote virus targets

KAUST Repository

Najera, Julia A.; Bustamante, Eduardo A.; Bortell, Nikki; Morsey, Brenda; Fox, Howard S.; Ravasi, Timothy; Marcondes, Maria Cecilia Garibaldi

2016-01-01

/function of innate immune cells and increase brain viral loads. Here, we examined changes in the gene expression profile of neuron-free microglial cell preparations isolated from the brain of macaques infected with the Simian Immunodeficiency Virus (SIV), a model

Zika Virus Tissue and Blood Compartmentalization in Acute Infection of Rhesus Macaques.

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Coffey, Lark L; Pesavento, Patricia A; Keesler, Rebekah I; Singapuri, Anil; Watanabe, Jennifer; Watanabe, Rie; Yee, JoAnn; Bliss-Moreau, Eliza; Cruzen, Christina; Christe, Kari L; Reader, J Rachel; von Morgenland, Wilhelm; Gibbons, Anne M; Allen, A Mark; Linnen, Jeff; Gao, Kui; Delwart, Eric; Simmons, Graham; Stone, Mars; Lanteri, Marion; Bakkour, Sonia; Busch, Michael; Morrison, John; Van Rompay, Koen K A

2017-01-01

Animal models of Zika virus (ZIKV) are needed to better understand tropism and pathogenesis and to test candidate vaccines and therapies to curtail the pandemic. Humans and rhesus macaques possess similar fetal development and placental biology that is not shared between humans and rodents. We inoculated 2 non-pregnant rhesus macaques with a 2015 Brazilian ZIKV strain. Consistent with most human infections, the animals experienced no clinical disease but developed short-lived plasma viremias that cleared as neutralizing antibody developed. In 1 animal, viral RNA (vRNA) could be detected longer in whole blood than in plasma. Despite no major histopathologic changes, many adult tissues contained vRNA 14 days post-infection with highest levels in hemolymphatic tissues. These observations warrant further studies to investigate ZIKV persistence and its potential clinical implications for transmission via blood products or tissue and organ transplants.

Metabolism of 14C-labeled doxylamine succinate (Bendectin) in the rhesus monkey (Macaca mulatta)

International Nuclear Information System (INIS)

Slikker, W. Jr.; Holder, C.L.; Lipe, G.W.; Korfmacher, W.A.; Thompson, H.C. Jr.; Bailey, J.R.

1986-01-01

The time-course of the metabolic fate of [ 14 C]doxylamine was determined after the p.o. administration of 13 mg/kg doxylamine succinate as Bendectin plus [ 14 C]doxylamine succinate to the rhesus monkey. Urine and plasma samples were analyzed by reversed-phase high performance liquid chromatography (HPLC), chemical derivatization, and mass spectrometry. The cumulative 48-hr urinary metabolic profile contained 81% of the administered radiolabeled dose and consisted of at least six radiolabeled peaks. They were peak 1: unknown polar metabolites (8% of dose); peak 2: 2-[1-phenyl-1-(2-pyridinyl)ethoxy] acetic acid, 1-[1-phenyl-1(2-pyridinyl)ethoxy] methanol, and another minor metabolite(s) (31%); peak 3: doxylamine-N-oxide (1%); peak 4a: N,N-didesmethyldoxylamine (17%); peak 4b: doxylamine (4%); and peak 5: N-desmethyldoxylamine (20%). The plasma metabolic profile was the same as the urinary profile except for the absence of doxylamine-N-oxide. The maximum plasma concentrations and elapsed time to attain these concentrations were as follows. Peak 1: 540 ng/mL, 4 hr; peak 2: 1700 ng/mL, 1 hr; peak 4a: 430 ng/mL, 4 hr; peak 4b: 930 ng/mL, 2 hr; and peak 5: 790 ng/mL, 2 hr. These data suggest that in the monkey, doxylamine metabolism follows at least four pathways: a minor pathway to the N-oxide; a minor pathway to unknown polar metabolites; a major pathway to mono- and didesmethyldoxylamine via successive N-demethylation; and a major pathway to side-chain cleavage products (peak 2) via direct side-chain oxidation and/or deamination

Heterochrony and cross-species intersensory matching by infant vervet monkeys.

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Shahin Zangenehpour

Full Text Available Understanding the evolutionary origins of a phenotype requires understanding the relationship between ontogenetic and phylogenetic processes. Human infants have been shown to undergo a process of perceptual narrowing during their first year of life, whereby their intersensory ability to match the faces and voices of another species declines as they get older. We investigated the evolutionary origins of this behavioral phenotype by examining whether or not this developmental process occurs in non-human primates as well.We tested the ability of infant vervet monkeys (Cercopithecus aethiops, ranging in age from 23 to 65 weeks, to match the faces and voices of another non-human primate species (the rhesus monkey, Macaca mulatta. Even though the vervets had no prior exposure to rhesus monkey faces and vocalizations, our findings show that infant vervets can, in fact, recognize the correspondence between rhesus monkey faces and voices (but indicate that they do so by looking at the non-matching face for a greater proportion of overall looking time, and can do so well beyond the age of perceptual narrowing in human infants. Our results further suggest that the pattern of matching by vervet monkeys is influenced by the emotional saliency of the Face+Voice combination. That is, although they looked at the non-matching screen for Face+Voice combinations, they switched to looking at the matching screen when the Voice was replaced with a complex tone of equal duration. Furthermore, an analysis of pupillary responses revealed that their pupils showed greater dilation when looking at the matching natural face/voice combination versus the face/tone combination.Because the infant vervets in the current study exhibited cross-species intersensory matching far later in development than do human infants, our findings suggest either that intersensory perceptual narrowing does not occur in Old World monkeys or that it occurs later in development. We argue that these

Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on signal transduction pathway-related protein expression in liver and cerebrum of rhesus monkey

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Ohta, Mari; Akema, Satoshi; Tsuzuki, Masami; Kubota, Shunichiro [Tokyo Univ. (Japan); Korenaga, Tatsumi; Fukusato, Toshio [Teikyo Univ. of School of Medicine, Tokyo (Japan); Asaoka, Kazuo [Kyoto Univ. (Japan); Murata, Nobuo [Teikyo Univ. of School of Medicine, Kawasaki (Japan); Nomizu, Motoyoshi [Hokkaido Univ., Sapporo (Japan); Arima, Akihiro [Shin Nippon Biomedical Laboratories, Ltd., Kagoshima (Japan)

2004-09-15

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is known to produce a wide range of toxic and biochemical effects in experimental animals, including immunological dysfunctions, chloracne, tetragenecity and carcinogenesis. Recently, the potential impact of dioxins on neurological disorders with particular focus on attention deficit hyperactivity disorder (ADHD) are concerned. Although a lot of information is available from studies in rodents, not much is known of the low dose effects of TCDD in non-human primates. In higher animals, dioxins are metabolized slowly, as evidenced by the estimated TCDD half-life of 5.8 to 14.1 years. Therefore, it is necessary to investigate the long-term effects of TCDD on human health. Considering the pronounced species differences observed in some studies of TCDD, the studies using primates are needed for assessment of TCDD exposure on human health. We have been studying the metabolism and the effects of single administration of TCDD on pregnant monkey (F0) and F1 rhesus monkey. The focus of the present study is to study the effects of TCDD on signal transduction pathway-related protein levels in various organs, especially in liver and brain of F0 monkeys.

Social facilitation of cognition in rhesus monkeys: audience vs. coaction

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Amélie J. Reynaud

2015-12-01

Full Text Available Social psychology has long established that the mere presence of a conspecific, be it an active co-performer (coaction effect, or a passive spectator (audience effect changes behavior in humans. Yet, the process mediating this fundamental social influence has so far eluded us. Brain research and its nonhuman primate animal model, the rhesus macaque, could shed new light on this long debated issue. For this approach to be fruitful, however, we need to improve our patchy knowledge about social presence influence in rhesus macaques. Here, seven adults (two dyads and one triad performed a simple cognitive task consisting in touching images to obtain food treats, alone versus in presence of a co-performer or a spectator. As in humans, audience sufficed to enhance performance to the same magnitude as coaction. Effect sizes were however 4 times larger than those typically reported in humans in similar tasks. Both findings are an encouragement to pursue brain and behavior research in the rhesus macaque to help solve the riddle of social facilitation mechanisms.

Increased infectivity in human cells and resistance to antibody-mediated neutralization by truncation of the SIV gp41 cytoplasmic tail

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Takeo eKuwata

2013-05-01

Full Text Available The role of antibodies in protecting the host from human immunodeficiency virus type 1 (HIV-1 infection is of considerable interest, particularly because the RV144 trial results suggest that antibodies contribute to protection. Although infection of nonhuman primates with simian immunodeficiency virus (SIV is commonly used as an animal model of HIV-1 infection, the viral epitopes that elicit potent and broad neutralizing antibodies to SIV have not been identified. We isolated a monoclonal antibody (MAb B404 that potently and broadly neutralizes various SIV strains. B404 targets a conformational epitope comprising the V3 and V4 loops of Env that intensely exposed when Env binds CD4. B404-resistant variants were obtained by passaging viruses in the presence of increasing concentration of B404 in PM1/CCR5 cells. Genetic analysis revealed that the Q733stop mutation, which truncates the cytoplasmic tail of gp41, was the first major substitution in Env during passage. The maximal inhibition by B404 and other MAbs were significantly decreased against a recombinant virus with a gp41 truncation compared with the parental SIVmac316. This indicates that the gp41 truncation was associated with resistance to antibody-mediated neutralization. The infectivities of the recombinant virus with the gp41 truncation were 7900-fold, 1000-fold, and 140-fold higher than those of SIVmac316 in PM1, PM1/CCR5, and TZM-bl cells, respectively. Immunoblotting analysis revealed that the gp41 truncation enhanced the incorporation of Env into virions. The effect of the gp41 truncation on infectivity was not obvious in the HSC-F macaque cell line, although the resistance of viruses harboring the gp41 truncation to neutralization was maintained. These results suggest that viruses with a truncated gp41 cytoplasmic tail were selected by increased infectivity in human cells and by acquiring resistance to neutralizing antibody.

Zika Virus Tissue and Blood Compartmentalization in Acute Infection of Rhesus Macaques.

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Lark L Coffey

Full Text Available Animal models of Zika virus (ZIKV are needed to better understand tropism and pathogenesis and to test candidate vaccines and therapies to curtail the pandemic. Humans and rhesus macaques possess similar fetal development and placental biology that is not shared between humans and rodents. We inoculated 2 non-pregnant rhesus macaques with a 2015 Brazilian ZIKV strain. Consistent with most human infections, the animals experienced no clinical disease but developed short-lived plasma viremias that cleared as neutralizing antibody developed. In 1 animal, viral RNA (vRNA could be detected longer in whole blood than in plasma. Despite no major histopathologic changes, many adult tissues contained vRNA 14 days post-infection with highest levels in hemolymphatic tissues. These observations warrant further studies to investigate ZIKV persistence and its potential clinical implications for transmission via blood products or tissue and organ transplants.

Associations between Parity, Hair Hormone Profiles during Pregnancy and Lactation, and Infant Development in Rhesus Monkeys (Macaca mulatta.

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Amanda M Dettmer

Full Text Available Studies examining hormones throughout pregnancy and lactation in women have been limited to single, or a few repeated, short-term measures of endocrine activity. Furthermore, potential differences in chronic hormonal changes across pregnancy/lactation between first-time and experienced mothers are not well understood, especially as they relate to infant development. Hormone concentrations in hair provide long-term assessments of hormone production, and studying these measures in non-human primates allows for repeated sampling under controlled conditions that are difficult to achieve in humans. We studied hormonal profiles in the hair of 26 female rhesus monkeys (Macaca mulatta, n=12 primiparous, to determine the influences of parity on chronic levels of cortisol (hair cortisol concentration, HCC and progesterone (hair progesterone concentration, HPC during early- to mid-pregnancy (PREG1, in late pregnancy/early lactation (PREG2/LACT1, and in peak lactation (LACT2. We also assessed infants' neurobehavioral development across the first month of life. After controlling for age and stage of pregnancy at the first hair sampling period, we found that HCCs overall peaked in PREG2/LACT1 (p=0.02, but only in primiparous monkeys (p<0.001. HPCs declined across pregnancy and lactation for all monkeys (p<0.01, and primiparous monkeys had higher HPCs overall than multiparous monkeys (p=0.02. Infants of primiparous mothers had lower sensorimotor reflex scores (p=0.02 and tended to be more irritable (p=0.05 and less consolable (p=0.08 in the first month of life. Moreover, across all subjects, HCCs in PREG2/LACT1 were positively correlated with irritability (r(s=0.43, p=0.03 and negatively correlated with sensorimotor scores (r(s=-0.41, p=0.04. Together, the present results indicate that primiparity influences both chronic maternal hormonal profiles and infant development. These effects may, in part, reflect differential reproductive and maternal effort in

Plasmodium simium/Plasmodium vivax infections in southern brown howler monkeys from the Atlantic Forest

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Daniela Camargos Costa

2014-08-01

Full Text Available Blood infection by the simian parasite, Plasmodium simium, was identified in captive (n = 45, 4.4% and in wild Alouatta clamitans monkeys (n = 20, 35% from the Atlantic Forest of southern Brazil. A single malaria infection was symptomatic and the monkey presented clinical and haematological alterations. A high frequency of Plasmodium vivax-specific antibodies was detected among these monkeys, with 87% of the monkeys testing positive against P. vivax antigens. These findings highlight the possibility of malaria as a zoonosis in the remaining Atlantic Forest and its impact on the epidemiology of the disease.

Utilizing a TLR5-Adjuvanted Cytomegalovirus as a Lentiviral Vaccine in the Nonhuman Primate Model for AIDS.

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Jesse D Deere

Full Text Available Despite tremendous progress in our understanding of human immunodeficiency virus (HIV natural history and advances in HIV treatment, there is neither an approved vaccine nor a cure for infection. Here, we describe the development and characterization of a novel replicating vaccine vector utilizing Cytomegalovirus (CMV and a TLR5 adjuvant. After partial truncation of the central, immunodominant hypervariable domain, flagellin (fliC from Salmonella was cloned downstream of a codon optimized gag gene from simian immunodeficiency virus (SIV and transiently expressed in telomerized rhesus fibroblast (TeloRF cells in culture. Lysates generated from these transfected cells induced the tumor necrosis factor alpha (TNF-α, in a mouse macrophage cell line, in a TLR5-dependent manner. The Gag/FliC expression construct was cloned into a bacterial artificial chromosome encoding the rhesus CMV (RhCMV genome, and infectious RhCMV was generated following transfection of TeloRF cells. This virus stably expressed an SIV Gag/FliC fusion protein through four serial passages. Lysates generated from infected cells induced TNF-α in a TLR5-dependent manner. Western blot analysis of infected cell lysates verified expression of a Gag/FliC fusion protein using a SIV p27 capsid monoclonal antibody. Lastly, rhesus macaques inoculated with this novel RhCMV virus demonstrated increased inflammatory responses at the site of inoculation seven days post-infection when compared to the parental RhCMV. These results demonstrate that an artificially constructed replicating RhCMV expressing an SIV Gag/FliC fusion protein is capable of activating TLR5 in a macrophage cell line in vitro and induction of an altered inflammatory response in vivo. Ongoing animals studies are aimed at determining vaccine efficacy, including subsequent challenge with pathogenic SIV.

Experimental cross-species infection of common marmosets by titi monkey adenovirus.

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Guixia Yu

Full Text Available Adenoviruses are DNA viruses that infect a number of vertebrate hosts and are associated with both sporadic and epidemic disease in humans. We previously identified a novel adenovirus, titi monkey adenovirus (TMAdV, as the cause of a fulminant pneumonia outbreak in a colony of titi monkeys (Callicebus cupreus at a national primate center in 2009. Serological evidence of infection by TMAdV was also found in a human researcher at the facility and household family member, raising concerns for potential cross-species transmission of the virus. Here we present experimental evidence of cross-species TMAdV infection in common marmosets (Callithrix jacchus. Nasal inoculation of a cell cultured-adapted TMAdV strain into three marmosets produced an acute, mild respiratory illness characterized by low-grade fever, reduced activity, anorexia, and sneezing. An increase in virus-specific neutralization antibody titers accompanied the development of clinical signs. Although serially collected nasal swabs were positive for TMAdV for at least 8 days, all 3 infected marmosets spontaneously recovered by day 12 post-inoculation, and persistence of the virus in tissues could not be established. Thus, the pathogenesis of experimental inoculation of TMAdV in common marmosets resembled the mild, self-limiting respiratory infection typically seen in immunocompetent human hosts rather than the rapidly progressive, fatal pneumonia observed in 19 of 23 titi monkeys during the prior 2009 outbreak. These findings further establish the potential for adenovirus cross-species transmission and provide the basis for development of a monkey model useful for assessing the zoonotic potential of adenoviruses.

Functional cure of SIVagm infection in rhesus macaques results in complete recovery of CD4+ T cells and is reverted by CD8+ cell depletion.

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Ivona Pandrea

2011-08-01

Full Text Available Understanding the mechanism of infection control in elite controllers (EC may shed light on the correlates of control of disease progression in HIV infection. However, limitations have prevented a clear understanding of the mechanisms of elite controlled infection, as these studies can only be performed at randomly selected late time points in infection, after control is achieved, and the access to tissues is limited. We report that SIVagm infection is elite-controlled in rhesus macaques (RMs and therefore can be used as an animal model for EC HIV infection. A robust acute infection, with high levels of viral replication and dramatic mucosal CD4(+ T cell depletion, similar to pathogenic HIV-1/SIV infections of humans and RMs, was followed by complete and durable control of SIVagm replication, defined as: undetectable VLs in blood and tissues beginning 72 to 90 days postinoculation (pi and continuing at least 4 years; seroreversion; progressive recovery of mucosal CD4(+ T cells, with complete recovery by 4 years pi; normal levels of T cell immune activation, proliferation, and apoptosis; and no disease progression. This "functional cure" of SIVagm infection in RMs could be reverted after 4 years of control of infection by depleting CD8 cells, which resulted in transient rebounds of VLs, thus suggesting that control may be at least in part immune mediated. Viral control was independent of MHC, partial APOBEC restriction was not involved in SIVagm control in RMs and Trim5 genotypes did not impact viral replication. This new animal model of EC lentiviral infection, in which complete control can be predicted in all cases, permits research on the early events of infection in blood and tissues, before the defining characteristics of EC are evident and when host factors are actively driving the infection towards the EC status.

Immunization of rhesus macaques with Echinococcus multilocularis recombinant 14-3-3 antigen leads to specific antibody response.

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Lampe, Karen; Gottstein, B; Becker, T; Stahl-Hennig, C; Kaup, F-J; Mätz-Rensing, K

2017-01-01

E. multilocularis (Em) is the etiologic agent of alveolar echinococcosis (AE), a severe and potentially fatal disease, primarily affecting the liver of and occurring in aberrant intermediate hosts, e.g., humans and non-human primates. Due to increasing numbers of spontaneous cases of AE in the Old World monkey colonies of the German Primate Center, the question arose as to whether vaccination of non-human primates may represent a useful prophylactic approach. In this pilot study, the recombinant antigen Em14-3-3, which has provided a 97 % protection against E. multilocularis challenge infection in rodent models, was used for the first time to immunize rhesus macaques. In order to increase immunogenicity, the antigen was formulated with different adjuvants including Quil A®, aluminum hydroxide (alum), and muramyl dipeptide (MDP). Also, different vaccination regimens were tested. All vaccinated animals developed antigen-specific antibodies. While Quil A® induced a local adverse reaction, alum proved to be the most potent adjuvant in terms of induced antibody levels, longevity as well as tolerability. In conclusion, our pilot study demonstrated that recombinant Em14-3-3 is safe and immunogenic in rhesus monkeys. As a next step, efficacy of the vaccination remains to be explored.

Change detection by rhesus monkeys (Macaca mulatta) and pigeons (Columba livia).

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Elmore, L Caitlin; Magnotti, John F; Katz, Jeffrey S; Wright, Anthony A

2012-08-01

Two monkeys (Macaca mulatta) learned a color change-detection task where two colored circles (selected from a 4-color set) were presented on a 4 × 4 invisible matrix. Following a delay, the correct response was to touch the changed colored circle. The monkeys' learning, color transfer, and delay transfer were compared to a similar experiment with pigeons. Monkeys, like pigeons (Columba livia), showed full transfer to four novel colors, and to delays as long as 6.4 s, suggesting they remembered the colors as opposed to perceptual based attentional capture process that may work at very short delays. The monkeys and pigeons were further tested to compare transfer with other dimensions. Monkeys transferred to shape and location changes, unlike the pigeons, but neither species transferred to size changes. Thus, monkeys were less restricted in their domain to detect change than pigeons, but both species learned the basic task and appear suitable for comparative studies of visual short-term memory. 2012 APA, all rights reserved

Immunoglobulins and complement in the skin of Rhesus monkeys immunized with X-irradiated cercariae of Schistosoma japonicum

International Nuclear Information System (INIS)

Li-Hsue, S.Y.; Hsue, H.F.; Hanson, H.O.

1981-01-01

Skin sections of Rhesus monkeys immunized with X-irradiated Schistosoma japonicum cercariae were stained by an unlabeled antibody enzyme method for the detection of IgG, IgM, IgA, IgE, and C3. While all of them could be found in the skin lesions, their distribution patterns varied with time and reactions. In whealing reaginic reactions, IgE appeared prominent, having an affinity to the mast cells. In Arthus-like reactions, IgG was predominant. IgG complexes were found on the schistosomula, on the walls of blood vessels, and in granulocytes near the schistosomula. In the late stage of Arthus-like reactions and in delayed hypersensitive reactions, IgA was predominant in granulocytes, mononuclear cells, and macrophages. Characteristics of each immunoglobulin pattern seemed to reflect its function in the effector mechanism. It may be speculated that these immunoglobulins and C3, together with effector cells, synergistically and sequentially destroy schistosomula in the skin. (orig.)

Immunoglobulins and complement in the skin of Rhesus monkeys immunized with X-irradiated cercariae of Schistosoma japonicum

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Li-Hsue, S.Y.; Hsue, H.F.; Hanson, H.O.

1981-01-01

Skin sections of Rhesus monkeys immunized with X-irradiated Schistosoma japonicum cercariae were stained by an unlabeled antibody enzyme method for the detection of IgG, IgM, IgA, IgE, and C3. While all of them could be found in the skin lesions, their distribution patterns varied with time and reactions. In whealing reaginic reactions, IgE appeared prominent, having an affinity to the mast cells. In Arthus-like reactions, IgG was predominant. IgG complexes were found on the schistosomula, on the walls of blood vessels, and in granulocytes near the schistosomula. In the late stage of Arthus-like reactions and in delayed hypersensitive reactions, IgA was predominant in granulocytes, mononuclear cells, and macrophages. Characteristics of each immunoglobulin pattern seemed to reflect its function in the effector mechanism. It may be speculated that these immunoglobulins and C3, together with effector cells, synergistically and sequentially destroy schistosomula in the skin.

Effect of spaceflight on the isotonic contractile properties of single skeletal muscle fibers in the rhesus monkey

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Fitts, R. H.; Romatowski, J. G.; Blaser, C.; De La Cruz, L.; Gettelman, G. J.; Widrick, J. J.

2000-01-01

Experiments from both Cosmos and Space Shuttle missions have shown weightlessness to result in a rapid decline in the mass and force of rat hindlimb extensor muscles. Additionally, despite an increased maximal shortening velocity, peak power was reduced in rat soleus muscle post-flight. In humans, declines in voluntary peak isometric ankle extensor torque ranging from 15-40% have been reported following long- and short-term spaceflight and prolonged bed rest. Complete understanding of the cellular events responsible for the fiber atrophy and the decline in force, as well as the development of effective countermeasures, will require detailed knowledge of how the physiological and biochemical processes of muscle function are altered by spaceflight. The specific purpose of this investigation was to determine the extent to which the isotonic contractile properties of the slow- and fast-twitch fiber types of the soleus and gastrocnemius muscles of rhesus monkeys (Macaca mulatta) were altered by a 14-day spaceflight.

Effects of Vector Backbone and Pseudotype on Lentiviral Vector-mediated Gene Transfer: Studies in Infant ADA-Deficient Mice and Rhesus Monkeys

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Carbonaro Sarracino, Denise; Tarantal, Alice F; Lee, C Chang I.; Martinez, Michele; Jin, Xiangyang; Wang, Xiaoyan; Hardee, Cinnamon L; Geiger, Sabine; Kahl, Christoph A; Kohn, Donald B

2014-01-01

Systemic delivery of a lentiviral vector carrying a therapeutic gene represents a new treatment for monogenic disease. Previously, we have shown that transfer of the adenosine deaminase (ADA) cDNA in vivo rescues the lethal phenotype and reconstitutes immune function in ADA-deficient mice. In order to translate this approach to ADA-deficient severe combined immune deficiency patients, neonatal ADA-deficient mice and newborn rhesus monkeys were treated with species-matched and mismatched vectors and pseudotypes. We compared gene delivery by the HIV-1-based vector to murine γ-retroviral vectors pseudotyped with vesicular stomatitis virus-glycoprotein or murine retroviral envelopes in ADA-deficient mice. The vesicular stomatitis virus-glycoprotein pseudotyped lentiviral vectors had the highest titer and resulted in the highest vector copy number in multiple tissues, particularly liver and lung. In monkeys, HIV-1 or simian immunodeficiency virus vectors resulted in similar biodistribution in most tissues including bone marrow, spleen, liver, and lung. Simian immunodeficiency virus pseudotyped with the gibbon ape leukemia virus envelope produced 10- to 30-fold lower titers than the vesicular stomatitis virus-glycoprotein pseudotype, but had a similar tissue biodistribution and similar copy number in blood cells. The relative copy numbers achieved in mice and monkeys were similar when adjusted to the administered dose per kg. These results suggest that this approach can be scaled-up to clinical levels for treatment of ADA-deficient severe combined immune deficiency subjects with suboptimal hematopoietic stem cell transplantation options. PMID:24925206

Effects of vector backbone and pseudotype on lentiviral vector-mediated gene transfer: studies in infant ADA-deficient mice and rhesus monkeys.

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Carbonaro Sarracino, Denise; Tarantal, Alice F; Lee, C Chang I; Martinez, Michele; Jin, Xiangyang; Wang, Xiaoyan; Hardee, Cinnamon L; Geiger, Sabine; Kahl, Christoph A; Kohn, Donald B

2014-10-01

Systemic delivery of a lentiviral vector carrying a therapeutic gene represents a new treatment for monogenic disease. Previously, we have shown that transfer of the adenosine deaminase (ADA) cDNA in vivo rescues the lethal phenotype and reconstitutes immune function in ADA-deficient mice. In order to translate this approach to ADA-deficient severe combined immune deficiency patients, neonatal ADA-deficient mice and newborn rhesus monkeys were treated with species-matched and mismatched vectors and pseudotypes. We compared gene delivery by the HIV-1-based vector to murine γ-retroviral vectors pseudotyped with vesicular stomatitis virus-glycoprotein or murine retroviral envelopes in ADA-deficient mice. The vesicular stomatitis virus-glycoprotein pseudotyped lentiviral vectors had the highest titer and resulted in the highest vector copy number in multiple tissues, particularly liver and lung. In monkeys, HIV-1 or simian immunodeficiency virus vectors resulted in similar biodistribution in most tissues including bone marrow, spleen, liver, and lung. Simian immunodeficiency virus pseudotyped with the gibbon ape leukemia virus envelope produced 10- to 30-fold lower titers than the vesicular stomatitis virus-glycoprotein pseudotype, but had a similar tissue biodistribution and similar copy number in blood cells. The relative copy numbers achieved in mice and monkeys were similar when adjusted to the administered dose per kg. These results suggest that this approach can be scaled-up to clinical levels for treatment of ADA-deficient severe combined immune deficiency subjects with suboptimal hematopoietic stem cell transplantation options.

Effects of damage to the suprachiasmatic area of the anterior hypothalamus on the daily melatonin and cortisol rhythms in the rhesus monkey

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Reppert, S.M.; Perlow, M.J.; Ungerleider, L.G.; Mishkin, M.; Tamarkin, L.; Orloff, D.G.; Hoffman, H.J.; Klein, D.C.

1981-12-01

The effects of lesions of the suprachiasmatic nucleus (SCN) on the circadian rhythms in melatonin and cortisol were examined in the rhesus monkey. The concentrations of the two hormones were monitored in cerebrospinal fluid (CSF) withdrawn from two sham-operated animals, two animals with complete bilateral SCN lesions, and two animals with partial SCN damage at 4 and 8 months after surgery. In the sham-operated animals, as in the intact animal, the daily melatonin rhythm was entrained to the daily light-dark cycle, was suppressed in constant light, and persisted in constant darkness. In contrast, neither animal with complete SCN ablation exhibited a daily pattern of CSF melatonin in diurnal lighting at 4 months after surgery nor were their melatonin levels at constant low values. Furthermore, CSF melatonin concentrations were not suppressed in either animal by constant light. Surprisingly, at 8 months after surgery, spectral analysis revealed a 24-hr component to the melatonin patterns for each animal with complete SCN ablation in both diurnal lighting and constant darkness. The two animals with partial SCN damage exhibited a daily melatonin rhythm in diurnal lighting, but constant light did not suppress CSF melatonin concentrations consistently. Daily rhythms persisted in both for a 6 1/2-d period of study in constant darkness. In contrast to the alterations in the melatonin rhythm after SCN damage, there was no apparent effect of either partial or complete SCN ablation on the daily CSF cortisol rhythm. These data indicate that, in the rhesus monkey, the SCN is important for the generation, photic entrainment, and photic suppression of the melatonin rhythm. However, circadian oscillators located outside of the SCN region may control the normal daily cortisol rhythm and perhaps the melatonin rhythm in the absence of the SCN.

Effects of damage to the suprachiasmatic area of the anterior hypothalamus on the daily melatonin and cortisol rhythms in the rhesus monkey

International Nuclear Information System (INIS)

Reppert, S.M.; Perlow, M.J.; Ungerleider, L.G.; Mishkin, M.; Tamarkin, L.; Orloff, D.G.; Hoffman, H.J.; Klein, D.C.

1981-01-01

The effects of lesions of the suprachiasmatic nucleus (SCN) on the circadian rhythms in melatonin and cortisol were examined in the rhesus monkey. The concentrations of the two hormones were monitored in cerebrospinal fluid (CSF) withdrawn from two sham-operated animals, two animals with complete bilateral SCN lesions, and two animals with partial SCN damage at 4 and 8 months after surgery. In the sham-operated animals, as in the intact animal, the daily melatonin rhythm was entrained to the daily light-dark cycle, was suppressed in constant light, and persisted in constant darkness. In contrast, neither animal with complete SCN ablation exhibited a daily pattern of CSF melatonin in diurnal lighting at 4 months after surgery nor were their melatonin levels at constant low values. Furthermore, CSF melatonin concentrations were not suppressed in either animal by constant light. Surprisingly, at 8 months after surgery, spectral analysis revealed a 24-hr component to the melatonin patterns for each animal with complete SCN ablation in both diurnal lighting and constant darkness. The two animals with partial SCN damage exhibited a daily melatonin rhythm in diurnal lighting, but constant light did not suppress CSF melatonin concentrations consistently. Daily rhythms persisted in both for a 6 1/2-d period of study in constant darkness. In contrast to the alterations in the melatonin rhythm after SCN damage, there was no apparent effect of either partial or complete SCN ablation on the daily CSF cortisol rhythm. These data indicate that, in the rhesus monkey, the SCN is important for the generation, photic entrainment, and photic suppression of the melatonin rhythm. However, circadian oscillators located outside of the SCN region may control the normal daily cortisol rhythm and perhaps the melatonin rhythm in the absence of the SCN

Comparison of the effects of 50 MeV/sub d → Be/ neutron and cobalt-60 irradiation of the kidneys of Rhesus monkeys

International Nuclear Information System (INIS)

Raulston, G.L.; Gray, K.N.; Gleiser, C.A.; Jardine, J.H.; Flow, B.L.; Huchton, J.I.; Bennett, K.R.; Hussey, D.H.

1978-01-01

Twenty rhesus monkeys had one kidney irradiated (after undergoing unilateral nephrectomies) with one of four doses: 960 or 1080 rads of 50 MeV/sub d→Be/ neutrons, or 2350 or 2700 rads of 60 Co. Whereas animals treated with the lower dose of neutrons or 60 Co are alive with relatively normal renal function, those treated with the higher dose of neutrons died of radiation nephritis. Animals treated with the higher dose of 60 Co developed radiation nephritis but survived. The physiological and histopathological changes of radiation nephritis secondary to neutron irradiation are not qualitatively different from those reported for radiation nephritis secondary to photon irradiation

Vaccination of rhesus macaques with a vif-deleted simian immunodeficiency virus proviral DNA vaccine

International Nuclear Information System (INIS)

Sparger, Ellen E.; Dubie, Robert A.; Shacklett, Barbara L.; Cole, Kelly S.; Chang, W.L.; Luciw, Paul A.

2008-01-01

Studies in non-human primates, with simian immunodeficiency virus (SIV) and simian/human immunodeficiency virus (SHIV) have demonstrated that live-attenuated viral vaccines are highly effective; however these vaccine viruses maintain a low level of pathogenicity. Lentivirus attenuation associated with deletion of the viral vif gene carries a significantly reduced risk for pathogenicity, while retaining the potential for virus replication of low magnitude in the host. This report describes a vif-deleted simian immunodeficiency virus (SIV)mac239 provirus that was tested as an attenuated proviral DNA vaccine by inoculation of female rhesus macaques. SIV-specific interferon-γ enzyme-linked immunospot responses of low magnitude were observed after immunization with plasmid containing the vif-deleted SIV provirus. However, vaccinated animals displayed strong sustained virus-specific T cell proliferative responses and increasing antiviral antibody titers. These immune responses suggested either persistent vaccine plasmid expression or low level replication of vif-deleted SIV in the host. Immunized and unvaccinated macaques received a single high dose vaginal challenge with pathogenic SIVmac251. A transient suppression of challenge virus load and a greater median survival time was observed for vaccinated animals. However, virus loads for vaccinated and unvaccinated macaques were comparable by twenty weeks after challenge and overall survival curves for the two groups were not significantly different. Thus, a vif-deleted SIVmac239 proviral DNA vaccine is immunogenic and capable of inducing a transient suppression of pathogenic challenge virus, despite severe attenuation of the vaccine virus

Choice between variable and fixed cocaine injections in male rhesus monkeys.

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Huskinson, S L; Freeman, K B; Petry, N M; Rowlett, J K

2017-08-01

The schedule of drug availability may enhance choice of a drug. In non-human subjects, reinforcers are chosen more often when available under variable schedules of reinforcement relative to fixed schedules. To determine whether variable-drug access is an important determinant of cocaine choice by manipulating the schedule, drug dose, and combination of schedule + dose. Four male rhesus monkeys chose between cocaine doses (0.025-0.4 mg/kg/injection). In control conditions, the schedule and dose of each drug delivery were fixed. In other conditions, the reinforcement schedule (i.e., variable-ratio schedule), dose of each cocaine delivery, or both were variable on one lever while all aspects on the other lever remained fixed. When cocaine dose was equal on average (0.1 mg/kg/injection), 2 of 4 subjects chose cocaine associated with the variable schedule more than the fixed schedule. All subjects chose the variable dose that was equal on average to the fixed dose, and this difference was statistically significant. Three of 4 subjects chose cocaine associated with the variable combination over the fixed option (when the dose was equal on average). During dose-response determinations (when dose on the variable and fixed options were not equal), making the schedule, dose, or both variable generally did not alter cocaine's potency as a reinforcer. While many factors contribute to drug choice, unpredictable drug access is a feature that may be common in the natural environment and could play a key role in the allocation of behavior to drug alternatives by patients with substance-use disorders.

Coreceptor use in nonhuman primate models of HIV infection.

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Sina, Silvana Tasca; Ren, Wuze; Cheng-Mayer, Cecilia

2011-01-27

SIV or SHIV infection of nonhuman primates (NHP) has been used to investigate the impact of coreceptor usage on the composition and dynamics of the CD4+ T cell compartment, mechanisms of disease induction and development of clinical syndrome. As the entire course of infection can be followed, with frequent access to tissue compartments, infection of rhesus macaques with CCR5-tropic SHIVs further allows for study of HIV-1 coreceptor switch after intravenous and mucosal inoculation, with longitudinal and systemic analysis to determine the timing, anatomical sites and cause for the change in envelope glycoprotein and coreceptor preference. Here, we review our current understanding of coreceptor use in NHPs and their impact on the pathobiological characteristics of the infection, and discuss recent advances in NHP studies to uncover the underlying selective pressures for the change in coreceptor preference in vivo.

Enhanced discriminative stimulus effects of Δ(9)-THC in the presence of cannabidiol and 8-OH-DPAT in rhesus monkeys.

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McMahon, Lance R

2016-08-01

Cannabidiol, a therapeutic with potential serotonin (5-hydroxytryptamine; 5-HT) 5-HT1A receptor agonist activity, is the second most prevalent cannabinoid in Cannabis after Δ(9)-THC. The extent to which cannabidiol modifies the effects of Δ(9)-THC has not been firmly established, especially with respect to abuse-related effects in rhesus monkeys where previously antagonistic interactions have been reported for some behavioral outcomes. Cannabidiol and the 5-HT1A receptor agonist (±)-8-hydroxy-2-(dipropylamino)tetralin hydrobromide (8-OH-DPAT) were tested in two separate discrimination assays in rhesus monkeys. One group (n=6) discriminated Δ(9)-tetrahydrocannabinol (Δ(9)-THC; 0.1mg/kg i.v.); a second group (n=6) discriminated the cannabinoid antagonist rimonabant (1mg/kg i.v.) while receiving Δ(9)-THC daily (1mg/kg/12hs.c.). Responding was maintained under a fixed ratio 5 schedule of stimulus-shock termination. Both training drugs dose-dependently increased the percentage of responses on the respective drug-associated levers. Cannabidiol (up to 17.8mg/kg) and 8-OH-DPAT (up to 0.178mg/kg) did not substitute for either training drug; however, both significantly increased the potency of Δ(9)-THC to produce discriminative stimulus effects. Moreover, 8-OH-DPAT significantly attenuated the discriminative stimulus effects of rimonabant, whereas cannabidiol did not modify the rimonabant discriminative stimulus. These results, which are consistent with cannabidiol lacking CB1 receptor agonist or antagonist activity in vivo, demonstrate enhancement of the effects of Δ(9)-THC by cannabidiol, albeit at cannabidiol amounts larger than those in Cannabis or cannabidiol-based therapeutics (nabiximols). In addition to showing that cannabidiol and a 5-HT1A receptor agonist have overlapping behavioral effects, the current results suggest that 5-HT1A agonism enhances the CB1 receptor-mediated effects of Δ(9)-THC. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Enhanced discriminative stimulus effects of Δ9-THC in the presence of cannabidiol and 8-OH-DPAT in rhesus monkeys

Science.gov (United States)

McMahon, Lance R.

2016-01-01

Background Cannabidiol, a therapeutic with potential serotonin (5-hydroxytryptamine; 5-HT) 5-HT1A receptor agonist activity, is the second most prevalent cannabinoid in Cannabis after Δ9-THC. The extent to which cannabidiol modifies the effects of Δ9-THC has not been firmly established, especially with respect to abuse-related effects in rhesus monkeys where previously antagonistic interactions have been reported for some behavioral outcomes. Methods Cannabidiol and the 5-HT1A receptor agonist (±)-8-hydroxy-2-(dipropylamino)tetralin hydrobromide (8-OH-DPAT) were tested in two separate discrimination assays in rhesus monkeys. One group (n=6) discriminated Δ9-tetrahydrocannabinol (Δ9-THC; 0.1 mg/kg i.v.); a second group (n=6) discriminated the cannabinoid antagonist rimonabant (1 mg/kg i.v.) while receiving Δ9-THC daily (1 mg/kg/12 h s.c.). Responding was maintained under a fixed ratio 5 schedule of stimulus-shock termination. Results Both training drugs dose-dependently increased the percentage of responses on the respective drug-associated levers. Cannabidiol (up to 17.8 mg/kg) and 8-OH-DPAT (up to 0.178 mg/kg) did not substitute for either training drug; however, both significantly increased the potency of Δ9-THC to produce discriminative stimulus effects. Moreover, 8-OH-DPAT significantly attenuated the discriminative stimulus effects of rimonabant, whereas cannabidiol did not modify the rimonabant discriminative stimulus. Conclusions These results, which are consistent with cannabidiol lacking CB1 receptor agonist or antagonist activity in vivo, demonstrate enhancement of the effects of Δ9-THC by cannabidiol, albeit at cannabidiol amounts larger than those in Cannabis or cannabidiol-based therapeutics (nabiximols). In addition to showing that cannabidiol and a 5-HT1A receptor agonist have overlapping behavioral effects, the current results suggest that 5-HT1A agonism enhances the CB1 receptor-mediated effects of Δ9-THC. PMID:27289270

Role of basal stress hormones and amygdala dimensions in stress coping strategies of male rhesus monkeys in response to a hazard-reward conflict

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Elaheh Tekieh

2017-08-01

Full Text Available Objective(s: In the present study the effect of stress on monkeys that had learned to retrieve food from a five-chamber receptacle, as well as the relationship between their behavior and the serum cortisol and epinephrine levels and relative size of the amygdala was evaluated. Materials and Methods: Six male rhesus monkeys were individually given access to the food reward orderly. They could easily retrieve the rewards from all chambers except for the chamber 4, which a brief, mild electric shock (3 V was delivered to them upon touching the chamber’s interior. The coping behaviors were video-recorded and analyzed offline. Baseline serum cortisol and epinephrine levels were measured before the experiments using monkey enzyme-linked immunosorbent assay kit. One week after the behavioral experiment, the monkeys’ brains were scanned using magnetic resonance imaging under general anesthesia. The cross-sectional area of the left amygdala in sagittal plane relative to the area of the whole brain in the same slice was evaluated by the planimetric method using ImageJ software. Results: Exposure to the distressing condition caused different behavioral responses. Monkeys with higher baseline levels of serum cortisol and epinephrine and larger amygdala behaved more violently in the face of stress, indicating adopting emotion-focused stress-coping strategies. Conversely, those with low plasma epinephrine, moderate cortisol, and smaller amygdala showed perseverative behavior, indicating a problem-focused coping style. Conclusion: In dealing with the same stress, different responses might be observed from nonhuman primates according to their cortisol and epinephrine levels as well as their amygdala dimensions.

Transcriptome analyses of rhesus monkey preimplantation embryos reveal a reduced capacity for DNA double-strand break repair in primate oocytes and early embryos

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Wang, Xinyi; Liu, Denghui; He, Dajian; Suo, Shengbao; Xia, Xian; He, Xiechao; Han, Jing-Dong J.; Zheng, Ping

2017-01-01

Preimplantation embryogenesis encompasses several critical events including genome reprogramming, zygotic genome activation (ZGA), and cell-fate commitment. The molecular basis of these processes remains obscure in primates in which there is a high rate of embryo wastage. Thus, understanding the factors involved in genome reprogramming and ZGA might help reproductive success during this susceptible period of early development and generate induced pluripotent stem cells with greater efficiency. Moreover, explaining the molecular basis responsible for embryo wastage in primates will greatly expand our knowledge of species evolution. By using RNA-seq in single and pooled oocytes and embryos, we defined the transcriptome throughout preimplantation development in rhesus monkey. In comparison to archival human and mouse data, we found that the transcriptome dynamics of monkey oocytes and embryos were very similar to those of human but very different from those of mouse. We identified several classes of maternal and zygotic genes, whose expression peaks were highly correlated with the time frames of genome reprogramming, ZGA, and cell-fate commitment, respectively. Importantly, comparison of the ZGA-related network modules among the three species revealed less robust surveillance of genomic instability in primate oocytes and embryos than in rodents, particularly in the pathways of DNA damage signaling and homology-directed DNA double-strand break repair. This study highlights the utility of monkey models to better understand the molecular basis for genome reprogramming, ZGA, and genomic stability surveillance in human early embryogenesis and may provide insights for improved homologous recombination-mediated gene editing in monkey. PMID:28223401

Different sensitivities to competitive inhibition of benzodiazepine receptor binding of {sup 11}C-iomazenil and {sup 11}C-flumazenil in rhesus monkey brain

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Inoue, Osamu; Hosoi, Rie; Kobayashi, Kaoru [Osaka Univ., Suita (Japan). Medical School; Itoh, Takashi; Gee, A.; Suzuki, Kazutoshi

2001-04-01

The in vivo binding kinetics of {sup 11}C-iomazenil were compared with those of {sup 11}C-flumazenil binding in rhesus monkey brain. The monkey was anesthetized with ketamine and intravenously injected with either {sup 11}C-iomazenil or {sup 11}C-flumazenil in combination with the coadministration of different doses of non-radioactive flumazenil (0, 5 and 20 {mu}g/kg). The regional distribution of {sup 11}C-iomazenil in the brain was similar to that of {sup 11}C-flumazenil, but the sensitivity of {sup 11}C-iomazenil binding to competitive inhibition by non-radioactive flumazenil was much less than that of {sup 11}C-flumazenil binding. A significant reduction in {sup 11}C-flumazenil binding in the cerebral cortex was observed with 20 {mu}g/kg of flumazenil, whereas a relatively smaller inhibition of {sup 11}C-iomazenil binding in the same region was observed with the same dose of flumazenil. These results suggest that {sup 11}C-flumazenil may be a superior radiotracer for estimating benzodiazepine receptor occupancy in the intact brain. (author)

HIV-1 and SIV Predominantly Use CCR5 Expressed on a Precursor Population to Establish Infection in T Follicular Helper Cells

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John Zaunders

2017-04-01

Full Text Available BackgroundT follicular helper (Tfh cells are increasingly recognized as a major reservoir of HIV infection that will likely need to be addressed in approaches to curing HIV. However, Tfh express minimal CCR5, the major coreceptor for HIV-1, and the mechanism by which they are infected is unclear. We have previously shown that macaque Tfh lack CCR5, but are infected in vivo with CCR5-using SIV at levels comparable to other memory CD4+ T cells. Similarly, human splenic Tfh cells are highly infected with HIV-1 DNA. Therefore, we set out to examine the mechanism of infection of Tfh cells.MethodologyTfh and other CD4+ T cell subsets from macaque lymph nodes and spleens, splenic Tfh from HIV+ subjects, and tonsillar Tfh from HIV-uninfected subjects were isolated by cell sorting prior to cell surface and molecular characterization. HIV proviral gp120 sequences were submitted to genotypic and phenotypic tropism assays. Entry of CCR5- and CXCR4-using viruses into Tfh from uninfected tonsillar tissue was measured using a fusion assay.ResultsPhylogenetic analysis, genotypic, and phenotypic analysis showed that splenic Tfh cells from chronic HIV+ subjects were predominantly infected with CCR5-using viruses. In macaques, purified CCR5+PD-1intermediate(int+ memory CD4+ T cells were shown to include pre-Tfh cells capable of differentiating in vitro to Tfh by upregulation of PD-1 and Bcl6, confirmed by qRT-PCR and single-cell multiplex PCR. Infected PD-1int cells survive, carry SIV provirus, and differentiate into PD-1hi Tfh after T cell receptor stimulation, suggesting a pathway for SIV infection of Tfh. In addition, a small subset of macaque and human PD-1hi Tfh can express low levels of CCR5, which makes them susceptible to infection. Fusion assays demonstrated CCR5-using HIV-1 entry into CCR5+ Tfh and pre-Tfh cells from human tonsils.ConclusionThe major route of infection of Tfh in macaques and humans appears to be via a CCR5-expressing pre-Tfh population

Adipose Tissue Is a Neglected Viral Reservoir and an Inflammatory Site during Chronic HIV and SIV Infection.

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Abderaouf Damouche

2015-09-01

Full Text Available Two of the crucial aspects of human immunodeficiency virus (HIV infection are (i viral persistence in reservoirs (precluding viral eradication and (ii chronic inflammation (directly associated with all-cause morbidities in antiretroviral therapy (ART-controlled HIV-infected patients. The objective of the present study was to assess the potential involvement of adipose tissue in these two aspects. Adipose tissue is composed of adipocytes and the stromal vascular fraction (SVF; the latter comprises immune cells such as CD4+ T cells and macrophages (both of which are important target cells for HIV. The inflammatory potential of adipose tissue has been extensively described in the context of obesity. During HIV infection, the inflammatory profile of adipose tissue has been revealed by the occurrence of lipodystrophies (primarily related to ART. Data on the impact of HIV on the SVF (especially in individuals not receiving ART are scarce. We first analyzed the impact of simian immunodeficiency virus (SIV infection on abdominal subcutaneous and visceral adipose tissues in SIVmac251 infected macaques and found that both adipocytes and adipose tissue immune cells were affected. The adipocyte density was elevated, and adipose tissue immune cells presented enhanced immune activation and/or inflammatory profiles. We detected cell-associated SIV DNA and RNA in the SVF and in sorted CD4+ T cells and macrophages from adipose tissue. We demonstrated that SVF cells (including CD4+ T cells are infected in ART-controlled HIV-infected patients. Importantly, the production of HIV RNA was detected by in situ hybridization, and after the in vitro reactivation of sorted CD4+ T cells from adipose tissue. We thus identified adipose tissue as a crucial cofactor in both viral persistence and chronic immune activation/inflammation during HIV infection. These observations open up new therapeutic strategies for limiting the size of the viral reservoir and decreasing low

Supplementary Material for: Methamphetamine abuse affects gene expression in brain-derived microglia of SIV-infected macaques to enhance inflammation and promote virus targets

KAUST Repository

Najera, Julia

2016-01-01

Abstract Background Methamphetamine (Meth) abuse is a major health problem linked to the aggravation of HIV- associated complications, especially within the Central Nervous System (CNS). Within the CNS, Meth has the ability to modify the activity/function of innate immune cells and increase brain viral loads. Here, we examined changes in the gene expression profile of neuron-free microglial cell preparations isolated from the brain of macaques infected with the Simian Immunodeficiency Virus (SIV), a model of neuroAIDS, and exposed to Meth. We aimed to identify molecular patterns triggered by Meth that could explain the detection of higher brain viral loads and the development of a pro-inflammatory CNS environment in the brain of infected drug abusers. Results We found that Meth alone has a strong effect on the transcription of genes associated with immune pathways, particularly inflammation and chemotaxis. Systems analysis led to a strong correlation between Meth exposure and enhancement of molecules associated with chemokines and chemokine receptors, especially CXCR4 and CCR5, which function as co-receptors for viral entry. The increase in CCR5 expression was confirmed in the brain in correlation with increased brain viral load. Conclusions Meth enhances the availability of CCR5-expressing cells for SIV in the brain, in correlation with increased viral load. This suggests that Meth is an important factor in the susceptibility to the infection and to the aggravated CNS inflammatory pathology associated with SIV in macaques and HIV in humans.

Protection of Rhesus Monkeys by a DNA Prime/Poxvirus Boost Malaria Vaccine Depends on Optimal DNA Priming and Inclusion of Blood Stage Antigens

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Weiss, Walter R.; Kumar, Anita; Jiang, George; Williams, Jackie; Bostick, Anthony; Conteh, Solomon; Fryauff, David; Aguiar, Joao; Singh, Manmohan; O'Hagan, Derek T.; Ulmer, Jeffery B.; Richie, Thomas L.

2007-01-01

Background We have previously described a four antigen malaria vaccine consisting of DNA plasmids boosted by recombinant poxviruses which protects a high percentage of rhesus monkeys against Plasmodium knowlesi (Pk) malaria. This is a multi-stage vaccine that includes two pre-erythrocytic antigens, PkCSP and PkSSP2(TRAP), and two erythrocytic antigens, PkAMA-1 and PkMSP-1(42kD). The present study reports three further experiments where we investigate the effects of DNA dose, timing, and formulation. We also compare vaccines utilizing only the pre-erythrocytic antigens with the four antigen vaccine. Methodology In three experiments, rhesus monkeys were immunized with malaria vaccines using DNA plasmid injections followed by boosting with poxvirus vaccine. A variety of parameters were tested, including formulation of DNA on poly-lactic co-glycolide (PLG) particles, varying the number of DNA injections and the amount of DNA, varying the interval between the last DNA injection to the poxvirus boost from 7 to 21 weeks, and using vaccines with from one to four malaria antigens. Monkeys were challenged with Pk sporozoites given iv 2 to 4 weeks after the poxvirus injection, and parasitemia was measured by daily Giemsa stained blood films. Immune responses in venous blood samples taken after each vaccine injection were measured by ELIspot production of interferon-γ, and by ELISA. Conclusions 1) the number of DNA injections, the formulation of the DNA plasmids, and the interval between the last DNA injection and the poxvirus injection are critical to vaccine efficacy. However, the total dose used for DNA priming is not as important; 2) the blood stage antigens PkAMA-1 and PkMSP-1 were able to protect against high parasitemias as part of a genetic vaccine where antigen folding is not well defined; 3) immunization with PkSSP2 DNA inhibited immune responses to PkCSP DNA even when vaccinations were given into separate legs; and 4) in a counter-intuitive result, higher

Canine distemper virus isolated from a monkey efficiently replicates on Vero cells expressing non-human primate SLAM receptors but not human SLAM receptor.

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Feng, Na; Liu, Yuxiu; Wang, Jianzhong; Xu, Weiwei; Li, Tiansong; Wang, Tiecheng; Wang, Lei; Yu, Yicong; Wang, Hualei; Zhao, Yongkun; Yang, Songtao; Gao, Yuwei; Hu, Guixue; Xia, Xianzhu

2016-08-02

In 2008, an outbreak of canine distemper virus (CDV) infection in monkeys was reported in China. We isolated CDV strain (subsequently named Monkey-BJ01-DV) from lung tissue obtained from a rhesus monkey that died in this outbreak. We evaluated the ability of this virus on Vero cells expressing SLAM receptors from dog, monkey and human origin, and analyzed the H gene of Monkey-BJ01-DV with other strains. The Monkey-BJ01-DV isolate replicated to the highest titer on Vero cells expressing dog-origin SLAM (10(5.2±0.2) TCID50/ml) and monkey-origin SLAM (10(5.4±0.1) TCID50/ml), but achieved markedly lower titers on human-origin SLAM cells (10(3.3±0.3) TCID50/ml). Phylogenetic analysis of the full-length H gene showed that Monkey-BJ01-DV was highly related to other CDV strains obtained during recent CDV epidemics among species of the Canidae family in China, and these Monkey strains CDV (Monkey-BJ01-DV, CYN07-dV, Monkey-KM-01) possessed a number of amino acid specific substitutions (E276V, Q392R, D435Y and I542F) compared to the H protein of CDV epidemic in other animals at the same period. Our results suggested that the monkey origin-CDV-H protein could possess specific substitutions to adapt to the new host. Monkey-BJ01-DV can efficiently use monkey- and dog-origin SLAM to infect and replicate in host cells, but further adaptation may be required for efficient replication in host cells expressing the human SLAM receptor.

Inhaled oxytocin amplifies both vicarious reinforcement and self reinforcement in rhesus macaques (Macaca mulatta).

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Chang, Steve W C; Barter, Joseph W; Ebitz, R Becket; Watson, Karli K; Platt, Michael L

2012-01-17

People attend not only to their own experiences, but also to the experiences of those around them. Such social awareness profoundly influences human behavior by enabling observational learning, as well as by motivating cooperation, charity, empathy, and spite. Oxytocin (OT), a neurosecretory hormone synthesized by hypothalamic neurons in the mammalian brain, can enhance affiliation or boost exclusion in different species in distinct contexts, belying any simple mechanistic neural model. Here we show that inhaled OT penetrates the CNS and subsequently enhances the sensitivity of rhesus macaques to rewards occurring to others as well as themselves. Roughly 2 h after inhaling OT, monkeys increased the frequency of prosocial choices associated with reward to another monkey when the alternative was to reward no one. OT also increased attention to the recipient monkey as well as the time it took to render such a decision. In contrast, within the first 2 h following inhalation, OT increased selfish choices associated with delivery of reward to self over a reward to the other monkey, without affecting attention or decision latency. Despite the differences in species typical social behavior, exogenous, inhaled OT causally promotes social donation behavior in rhesus monkeys, as it does in more egalitarian and monogamous ones, like prairie voles and humans, when there is no perceived cost to self. These findings potentially implicate shared neural mechanisms.

Synthesis, characterization, and first successful monkey imaging studies of metabotropic glutamate receptor subtype 5 (mGluR5) PET radiotracers.

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Hamill, Terence G; Krause, Stephen; Ryan, Christine; Bonnefous, Celine; Govek, Steve; Seiders, T Jon; Cosford, Nicholas D P; Roppe, Jeffrey; Kamenecka, Ted; Patel, Shil; Gibson, Raymond E; Sanabria, Sandra; Riffel, Kerry; Eng, Waisi; King, Christopher; Yang, Xiaoqing; Green, Mitchell D; O'Malley, Stacey S; Hargreaves, Richard; Burns, H Donald

2005-06-15

Three metabotropic glutamate receptor subtype 5 (mGluR5) PET tracers have been labeled with either carbon-11 or fluorine-18 and their in vitro and in vivo behavior in rhesus monkey has been characterized. Each of these tracers share the common features of high affinity for mGluR5 (0.08-0.23 nM vs. rat mGluR5) and moderate lipophilicity (log P 2.8-3.4). Compound 1b was synthesized using a Suzuki or Stille coupling reaction with [11C]MeI. Compounds 2b and 3b were synthesized by a SNAr reaction using a 3-chlorobenzonitrile precursor. Autoradiographic studies in rhesus monkey brain slices using 2b and 3b showed specific binding in cortex, caudate, putamen, amygdala, hippocampus, most thalamic nuclei, and lower binding in the cerebellum. PET imaging studies in monkey showed that all three tracers readily enter the brain and provide an mGluR5-specific signal in all gray matter regions, including the cerebellum. The specific signal observed in the cerebellum was confirmed by the autoradiographic studies and saturation binding experiments that showed tracer binding in the cerebellum of rhesus monkeys. In vitro metabolism studies using the unlabeled compounds showed that 1a, 2a, and 3a are metabolized slower by human liver microsomes than by monkey liver microsomes. In vivo metabolism studies showed 3b to be long-lived in rhesus plasma with only one other more polar metabolite observed. (c) 2005 Wiley-Liss, Inc.

The frontal eye fields limit the capacity of visual short-term memory in rhesus monkeys.

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Lee, Kyoung-Min; Ahn, Kyung-Ha

2013-01-01

The frontal eye fields (FEF) in rhesus monkeys have been implicated in visual short-term memory (VSTM) as well as control of visual attention. Here we examined the importance of the area in the VSTM capacity and the relationship between VSTM and attention, using the chemical inactivation technique and multi-target saccade tasks with or without the need of target-location memory. During FEF inactivation, serial saccades to targets defined by color contrast were unaffected, but saccades relying on short-term memory were impaired when the target count was at the capacity limit of VSTM. The memory impairment was specific to the FEF-coded retinotopic locations, and subject to competition among targets distributed across visual fields. These results together suggest that the FEF plays a crucial role during the entry of information into VSTM, by enabling attention deployment on targets to be remembered. In this view, the memory capacity results from the limited availability of attentional resources provided by FEF: The FEF can concurrently maintain only a limited number of activations to register the targets into memory. When lesions render part of the area unavailable for activation, the number would decrease, further reducing the capacity of VSTM.