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PubMed2001

Comparison of the frequencies of major histocompatibility (MHC) class-II DQA1 and DQB1 alleles in Indian and Chinese rhesus macaques (Macaca mulatta).

The major histocompatibility complex (MHC) comprises related gene families, some of which are highly polymorphic, whose protein products mediate immune response. Rhesus macaques (Macaca mulatta) are a vital animal model for research in human diseases and are native to regions extending from Afghanistan in the west to the Eastern Plains of China and from Peking to the north, southward through islands of Southeast Asia. The distributions of MHC class-II Mamu DQA1 and Mamu DQB1 alleles in two groups of domestically bred rhesus macaques of Indian and Chinese origin and the Mamu DQA1 genotypes of a small number of Burmese rhesus macaques were compared. Major allelic differences were observed between the Indian and Chinese rhesus macaques, and gene diversity decreased from east to west. These and other intra-specific genetic differences among regional populations of rhesus macaques might influence the outcome of biomedical research in which they are used as subjects, and illustrate the importance of completely genetically characterizing subjects used as animal models in biomedical research.

Alleles↗

PubMed1991

The effects of two novel objects on the behavior of singly caged adult rhesus macaques.

Six female and six male adult rhesus macaques were given sticks and nylon balls as an attempt at simple cage enrichment. A latin square design was used to compare behavior during separate 4-week periods with each object and during a control period with no object. Frequency and duration of 15 different behaviors were recorded. Resting was the most common activity which decreased slightly in duration when the stick or nylon ball was present (P less than 0.02). The mean duration of stick use was longer than that of the nylon ball (P less than 0.01). No other behaviors changed significantly, including the frequency of abnormal behaviors such as self-abuse, stereotypic acts, and bizarre postures. Generally, these objects were used infrequently and led to few changes in the behavior of singly-caged adult rhesus macaques. However, they did appear to stimulate activity for some individuals.

Animals↗

PubMed1998

Auditory brainstem responses in a Rhesus Macaque model of neuro-AIDS.

Nine rhesus macaques (Macaca mulatta) were inoculated with a combination of two passaged strains of SIVmac (R71 and 17E), both of which are known to be neurovirulent. Auditory brainstem responses (ABRs) were recorded at regular intervals from these animals both before and after inoculation. Increases in ABR peak and interpeak latency were observed corresponding to progression of SIV disease. Post-inoculation increases in latency were observed for all five peaks of the ABR and for interpeak intervals I-V and III-V. The largest increases in latency were associated with end-stage disease. Within 14 weeks of inoculation, all but two animals developed end-stage simian AIDS and were euthanized. Histopathological examination revealed multifocal lesions in the cerebral gray and white matter as well as in the auditory structures of the brainstem. In most animals, ABR changes were accompanied by evidence of underlying neuropathology. However, cases of severe neuropathology with no ABR abnormalities and vice versa were also noted. Though in a much shorter time frame, SIVmac R71/17E produced both physiological and histopathological abnormalities similar to those associated with HIV disease in humans. These results further support the SIVmac R71/17E infected rhesus macaque as an animal model of HIV related neurological disease in humans.

AIDS Dementia Complex↗

PubMed1999

Isolation, characterization, cDNA cloning, and antimicrobial properties of two distinct subfamilies of alpha-defensins from rhesus macaque leukocytes.

Experiments to isolate and characterize rhesus macaque myeloid alpha-defensins (RMADs) were conducted. Seven RMAD peptides were isolated and sequenced, and the cDNAs encoding six of these peptides and one other alpha-defensin from bone marrow were also characterized. Four of the RMADs were found to be highly similar to human neutrophil alpha-defensins HNP-1 to HNP-3, while the remaining four peptides were much more similar to human enteric alpha-defensin HD-5. Two alpha-defensin pairs differed only by the presence or absence of an additional arginine at the amino termini of their mature peptides, indicative of alternate posttranslational processing. The primary translation products of RMAD-1 to -8 are 94- and 96-amino-acid prepropeptides that are highly similar to those of human alpha-defensins. Immunolocalization experiments revealed a granular cytoplasmic pattern in the cytoplasms of neutrophils, indistinguishable from the pattern observed after immunostaining of human myeloid alpha-defensins in polymorphonuclear leukocytes. Each of the purified peptides was tested for its in vitro activities against Staphylococcus aureus 502a, Listeria monocytogenes EGD, Escherichia coli ML35, and Cryptococcus neoformans 271A. Several of the peptides were microbicidal for the gram-positive bacteria and C. neoformans at defensin concentrations in the range of 2 to 5 microM. All of the peptides were bacteriostatic against E. coli, but none were bactericidal for this organism. This study is the first to characterize the sequences and activities of alpha-defensins from nonhuman primates, data that should aid in delineating the role of these peptides in rhesus macaque host defense.

Amino Acid Sequence↗

PubMed2005

X-ray crystallographic characterization of rhesus macaque MHC Mamu-A*02 complexed with an immunodominant SIV-Gag nonapeptide.

Simian immunodeficiency virus (SIV) in the rhesus macaque is regarded as a classic animal model, playing a crucial role in HIV vaccine strategies and therapeutics by characterizing various cytotoxic T-lymphocyte (CTL) responses in macaque monkeys. However, the availability of well documented structural reports focusing on rhesus macaque major histocompatibility complex class I (MHC I) molecules remains extremely limited. Here, a complex of the rhesus macaque MHC I molecule (Mamu-A*02) with human beta2m and an immunodominant SIV-Gag nonapeptide, GESNLKSLY (GY9), has been crystallized. The crystal diffracts X-rays to 2.7 A resolution and belongs to space group C2, with unit-cell parameters a = 124.11, b = 110.45, c = 100.06 A, and contains two molecules in the asymmetric unit. The availability of the structure, which is being solved by molecular replacement, will provide new insights into rhesus macaque MHC I (Mamu-A*02) presenting pathogenic SIV peptides.

Animals↗

PubMed1995

Anti-human gonadotropin antibodies generated during in vitro fertilization (IVF)-related cycles: effect on fertility of rhesus macaques.

Administration of human gonadotropins such as hFSH, hLH, and hCG to rhesus macaques can result in formation of anti-human gonadotropin antibodies. To determine whether the presence of these antibodies interferes with subsequent fertility, sixteen female rhesus macaques (Macaca mulatta) with known antibody levels were bred with male rhesus macaques. The presence of antibodies did not interfere with conception or maintenance of pregnancy. Furthermore, antibody titers did not increase during gestation or following the resolution of pregnancy.

Animals↗

PubMed1997

Characterization of the onset of menopause in the rhesus macaque.

The objective of this study was to assess ovarian activity in a cohort of aged female rhesus macaques. Menstrual records for 26 rhesus macaques ages 20-29 yr were evaluated over a 1-yr period, and daily urinary estrone conjugate (E1C) and pregnanediol-3-glucuronide (Hygeia [Hy]-PdG) levels were determined for 12 wk. Each animal was categorized as either pre-, peri-, or postmenopausal based on menstrual and hormonal data. Eleven animals (mean age 22.5 yr) were premenopausal, thirteen (mean age 24 yr) were perimenopausal, and two (mean age 29.5 yr) were postmenopausal. Hormone profiles for perimenopausal animals reveal prolonged follicular phases and/or a lack of patterned Hy-PdG dynamics. Breakthrough bleeding occurred in four of these perimenopausal animals. The postmenopausal animals were amenorrheic and exhibited low E1C levels (less than 10 ng/mg creatinine). The results of this study illustrate that the decline of ovarian function in female macaques during the third decade of life parallels the menstrual and hormonal events associated with the climacteric in women, and that menopause does occur in rhesus macaques.

Aging↗

PubMed1990

Immunization with a live, attenuated simian immunodeficiency virus (SIV) prevents early disease but not infection in rhesus macaques challenged with pathogenic SIV.

An infectious, virulence-attenuated molecular clone of simian immunodeficiency virus (SIV), SIVMAC-1A11, was derived from an SIV isolate that causes fatal immunodeficiency in rhesus macaques. When inoculated intravenously in rhesus macaques, SIVMAC-1A11 induced transient viremia (1 to 6 weeks) without clinical disease and a persistent humoral antibody response. The antibodies were directed mainly against the viral envelope glycoproteins, as determined by immunoblots and virus neutralization. The potential of this virulence-attenuated virus to protect against intravenous challenge with a pathogenic SIVMAC strain was assessed. Five rhesus macaques were each given two intravenous inoculations with SIVMAC-1A11 7 months apart. Three of the five immunized monkeys and four naive control animals were then challenged with 100 to 1,000 100% animal infectious doses of pathogenic SIVMAC. All seven animals became persistently viremic following the challenge. Four of four unimmunized animals developed severe clinical signs of simian acquired immunodeficiency syndrome by 38 to 227 days after challenge and were euthanatized 91 to 260 days postchallenge. However, no signs of illness were seen in immunized monkeys until 267 to 304 days postchallenge, when two of three immunized animals developed mild thrombocytopenia and lymphopenia; one of these animals died with clinical signs of simian immunodeficiency disease at 445 days after challenge. The two SIVMAC-1A11-immunized monkeys that were not challenged were healthy and antibody positive 22 months after the initial immunization. Thus, although live SIVMAC-1A11 was immunogenic and did not induce any disease, it failed to protect rhesus macaques against infection with a moderately high dose of pathogenic virus. However, immunization prevented severe, early disease and prolonged the lives of monkeys subsequently infected with pathogenic SIV.

Animals↗

PubMed2005

Cloning, sequencing and characterization of lentiviral-mediated expression of rhesus macaque (Macaca mulatta) interleukin-2 receptor alpha cDNA.

The rhesus macaque CD25 (RhCD25) cDNA isolated from rhesus PBMCs was found to share 95.5 and 91.9% homology with the human orthologue at the nucleotide and amino acid levels, respectively. Comparative sequence analyses suggest that both human CD25 (HuCD25) and RhCD25 share identity for most of the critical amino acids previously identified to be essential for viable folding and IL-2 ligand binding. The human leukemic cell line, HH, deficient for IL-2Ralpha was transduced with a lentiviral vector (LV) engineered to express RhCD25 (HH-RhCD25). RhCD25 was characterized for expression by flow cytometric analyses, ELISA, Western blotting, functional signalling, and biological assays in comparison to HuCD25. In summary, vectors expressing the RhCD25 cDNA can be used as a tool to aid in the characterization of soluble CD25 in non-human primate studies, and to provide a tempting alternative as an autologous cell surface marker in rhesus macaque gene therapy and bone marrow transplantation studies.

Amino Acid Sequence↗

PubMed1990

Comparison of SIV/SMM replication in CD4+ T cell and monocyte/macrophage cultures from rhesus macaques and sooty mangabeys.

Monocytes from SIV/SMM infected sooty mangabeys and rhesus macaques were incubated in vitro with live SIV/SMM. The reverse transcriptase (RT) activity in the supernatant fluids of the monocyte cultures of the former species was higher than the RT activity in the latter species. No differences were found in the supernatant fluid of similar cultures of CD4+ T cells from both these species. Autologous (but not allogeneic) CD8+ T cells from SIV infected mangabeys and rhesus macaques inhibited SIV replication in vitro. The suppression appeared more marked in monocytes from the mangabey species. These in vitro differences may relate to the clinically asymptomatic state of the sooty mangabeys and the disease-susceptible state of the rhesus macaques.

Animals↗

PubMed2007

Genotyping and segregation analyses indicate the presence of only two functional MIC genes in rhesus macaques.

MIC molecules are stress-inducible ligands of the activating receptor NKG2D, which is expressed on natural killer cells and subsets of T lymphocytes. In rhesus macaques (Macaca mulatta), three different MIC sequences (MIC1, MIC2, MIC3) have been described that are closely related to but, according to phylogenetic analysis, do not represent orthologues of the human MICA and MICB genes. Although a single haplotype of the rhesus macaque Mhc (Mamu) has been completely sequenced, it remained unknown so far whether these three sequences are derived from two or three Mamu-MIC genes. We genotyped a cohort of 115 rhesus macaque individuals for the presence of MIC1, MIC2, and MIC3 sequences and analysed the segregation in families. All individuals were positive for MIC2, whereas only 66.1 and 80.9 % were positive for MIC1 and MIC3, respectively. MIC1 and MIC3 sequences segregated in offspring, indicating that they behave as alleles. Thus, we conclude that two MIC genes are present in the rhesus macaque Mhc, which we propose to designate as Mamu-MICA (MIC1 and MIC3) and Mamu-MICB (MIC2). "MIC1" and "MIC3" are regarded as divergent allelic lineages of the Mamu-MICA gene. Mamu-MIC genotyping of DNA of a cohort of 68 experimentally simian immunodeficiency virus (SIV)-infected rhesus macaques revealed no significant association of either of the two Mamu-MICA allelic lineages with differences in progression to AIDS-like symptoms.

Animals↗

PubMed2004

Amino acid domains control the circulatory residence time of primate acetylcholinesterases in rhesus macaques (Macaca mulatta).

An array of 13 biochemically well defined molecular forms of bovine, human and newly cloned rhesus macaque (Macaca mulatta) AChEs (acetylcholinesterases) differing in glycosylation and subunit assembly status were subjected to comparative pharmacokinetic studies in mice and rhesus macaques. The circulatory lifetimes of recombinant bovine, macaque and human AChEs in mice were governed by previously determined hierarchical rules; the longest circulatory residence time was obtained when AChE was fully sialylated and tetramerized [Kronman, Chitlaru, Elhanany, Velan and Shafferman (2000) J. Biol. Chem. 275, 29488-29502; Chitlaru, Kronman, Velan and Shafferman (2001) Biochem. J. 354, 613-625]. In rhesus macaques, bovine molecular forms still obeyed the same hierarchical rules, whereas primate AChEs showed significant deviation from this behaviour. Residence times of human and rhesus AChEs were effectively extended by extensive sialylation, but subunit tetramerization and N-glycan addition had a marginal effect on their circulatory longevity in macaques. It appears that the major factor responsible for the differential pharmacokinetics of bovine and primate AChEs in macaques is related to differences in primary structure, suggesting the existence of a specific mechanism for the circulatory clearance of primate AChEs in rhesus macaques. The 35 amino acids that differ between bovine and primate AChEs are clustered within three defined domains, all located at the enzyme surface, and may therefore mediate the facilitated removal of primate cholinesterases specifically from the circulation of monkeys. These surface domains can be effectively masked by poly(ethylene glycol) appendage, resulting in the generation of chemically modified human and macaque AChEs that reside in the circulation for extraordinarily long periods of time (mean residence time of 10000 min). This extended residence time is similar to that displayed by native macaque butyrylcholinesterase (9950 min), which is the prevalent cholinesterase form in the circulation of adult macaques.

Acetylcholinesterase↗

PubMed2004

Sequence of beta(2)-microglobulin from rhesus macaque ( Macaca mulatta) includes an allelic variation in the 3'-untranslated region.

The rhesus macaque ( Macaca mulatta) has become a popular animal model for several human infectious diseases, such as HIV (modeled by SIV infection), hepatitis, and malaria. Investigation of T-cell responses in experimental infectious diseases in rhesus macaques has benefited from an expanding understanding of the diversity of macaque MHC class I heavy chains and the restriction of antigen presentation by macaque class I molecules. Here we add to this understanding with the first nucleotide sequences of M. mulatta beta(2)-microglobulin (beta(2)m) mRNA, including a portion of the 3'-untranslated region (3'UTR). In pairwise comparison, the beta(2)m protein of M. mulatta differs from human and chimpanzee beta(2)m by nine amino-acid substitutions (92% identity), and from Macaca fascicularis by one amino-acid difference in the signal peptide region (99% identity). Allelic variations were identified at one site in the 3'UTR. A structural analysis of human or chimpanzee beta(2)m and M. mulatta beta(2)m suggests that the differences cluster in three solvent-exposed clusters and do not involve contacts with the class I heavy chain. We predict that human and macaque beta(2)m should bind interchangeably with the class I heavy chains of the other species, and show that four M. mulatta class I alleles form cell surface complexes with human beta(2)m. Further, we predict that W6/32 (a monoclonal antibody that recognizes a combined epitope of some class I heavy chains and beta(2)m with a subtle species dependence) should bind similarly human or macaque class I molecules that are bound with beta(2)m of either species, supported by evidence of recognition of both heterologous and homologous complexes of macaque class I heavy chains. Our findings contribute to the growing understanding of rhesus macaque histocompatibility antigens and antigen presentation, and to the phylogeny of beta(2)m in primates.

3' Untranslated Regions↗

PubMedDate not supplied

PET studies of cerebral glucose metabolism in conscious rhesus macaques.

A growing body of evidence suggests that rhesus macaques may be a good model of human brain aging. We used positron emission tomography (PET) and 18F-fluorodeoxyglucose (FDG) to measure regional cerebral metabolic rates for glucose (rCMRglc) in young and aged rhesus macaques to determine if age-related decreases, such as those reported in humans, also occur in macaques. Whereas the aged animals had lower metabolic rates in every brain region studied, the largest differences were in left temporal cortex. The largest differences were also observed in left temporal cortex when relative rCMRglc values were used. Both rCMRglc and relative rCMRglc were marked by substantial individual variation within the aged group. This variation may parallel the variation observed in behavioral studies. Future studies that include both PET and behavioral measures should help determine if there is a relationship between age-related changes in rCMRglc and behavior.

Aging↗

PubMed2007

A replication-competent adenovirus-human immunodeficiency virus (Ad-HIV) tat and Ad-HIV env priming/Tat and envelope protein boosting regimen elicits enhanced protective efficacy against simian/human immunodeficiency virus SHIV89.6P challenge in rhesus macaques.

We previously demonstrated that replication-competent adenovirus (Ad)-simian immunodeficiency virus (SIV) recombinant prime/protein boost regimens elicit potent immunogenicity and strong, durable protection of rhesus macaques against SIV(mac251). Additionally, native Tat vaccines have conferred strong protection against simian/human immunodeficiency virus SHIV(89.6P) challenge of cynomolgus monkeys, while native, inactivated, or vectored Tat vaccines have failed to elicit similar protective efficacy in rhesus macaques. Here we asked if priming rhesus macaques with replicating Ad-human immunodeficiency virus (HIV) tat and boosting with the Tat protein would elicit protection against SHIV(89.6P). We also evaluated a Tat/Env regimen, adding an Ad-HIV env recombinant and envelope protein boost to test whether envelope antibodies would augment acute-phase protection. Further, expecting cellular immunity to enhance chronic viremia control, we tested a multigenic group: Ad-HIV tat, -HIV env, -SIV gag, and -SIV nef recombinants and Tat, Env, and Nef proteins. All regimens were immunogenic. A hierarchy was observed in enzyme-linked immunospot responses (with the strongest response for Env, followed by Gag, followed by Nef, followed by Tat) and antibody titers (with the highest titer for Env, followed by Tat, followed by Nef, followed by Gag). Following intravenous SHIV(89.6P) challenge, all macaques became infected. Compared to controls, no protection was seen in the Tat-only group, confirming previous reports for rhesus macaques. However, the multigenic group blunted acute viremia by approximately 1 log (P = 0.017), and both the multigenic and Tat/Env groups reduced chronic viremia by 3 and 4 logs, respectively, compared to controls (multigenic, P = 0.0003; Tat/Env, P < 0.0001). The strikingly greater reduction in the Tat/Env group than in the multigenic group (P = 0.014) was correlated with Tat and Env binding antibodies. Since prechallenge anti-Env antibodies lacked SHIV(89.6P)-neutralizing activity, other functional anti-Env and anti-Tat activities are under investigation, as is a possible synergy between the Tat and Env immunogens.

Adenoviridae↗

PubMed1991

Catecholamines and uterine activity rhythms in the pregnant rhesus macaque.

This study was designed to examine the relationship between uterine contractile rhythms with maternal plasma and amniotic fluid catecholamine concentrations in the pregnant rhesus macaque. Six chronically catheterized rhesus macaques were maintained in a vest and tether system and exposed to a 12L:12D cycle. Continuous uterine activity recordings demonstrated a contractile pattern with peak activity at 2200 h (p less than 0.05). Paired maternal plasma and amniotic fluid samples were collected at 3-h intervals for 24 h between Days 131 and 148 of gestation. Samples were analyzed for norepinephrine, epinephrine, and dopamine by HPLC. Maximum plasma concentrations across the 24-h periods for norepinephrine (633 +/- 230; mean pg/ml +/- SEM) and dopamine (378 +/- 110) were observed at 2100 h and epinephrine (408 +/- 95) at 1200 h, but these values were not significant. The maximum amniotic fluid values were 378 +/- 126, 267 +/- 190, and 556 +/- 87 pg/ml for norepinephrine, epinephrine and dopamine, respectively. However, concentrations across 24 h did not differ. Neither maternal plasma nor amniotic fluid catecholamine concentrations were correlated with uterine activity rhythms. Therefore, we conclude that the nocturnal uterine activity in the rhesus macaque is not related to maternal arterial or amniotic fluid catecholamine concentrations.

Amniotic Fluid↗

PubMed1977

Comparison of cardiorenal functions between women and female rhesus macaques.

Selected cardiorenal functions for conscious and chaired rhesus macaques were compared directly and indirectly with corrections for body weights and surface areas to well-established base-line values for human subjects. Certain functional differences between species and conditions of measurement do not allow all experimental results from the rhesus macaque to be extrapolated to man. However, this comparative study provides evidence that can be useful in attempting to evaluate cardiorenal data from macaques in relationship to human studies.

Animals↗

PubMed2003

Infectious agent and immune response characteristics of chronic enterocolitis in captive rhesus macaques.

Chronic enterocolitis is the leading cause of morbidity in colonies of captive rhesus macaques (Macaca mulatta). This study's aim was to identify the common enteric pathogens frequently associated with chronic enterocolitis in normal, immunocompetent rhesus monkeys and to elucidate the influence of this clinical syndrome on the host immune system. We analyzed the fecal specimens from 100 rhesus macaques with or without clinical symptoms of chronic diarrhea. Retrospective analysis revealed an increased incidence of Campylobacter spp. (Campylobacter coli and Campylobacter jejuni), Shigella flexneri, Yersinia enterocolitica, adenovirus, and Strongyloides fulleborni in samples collected from animals with chronic diarrhea (P < 0.05). The presence of additional enteric pathogens, such as Escherichia coli, carrying the eaeA intimin or Stx2c Shiga toxin virulence genes, Balantidium coli, Giardia lamblia, Enterocytozoon bieneusi, and Trichuris trichiura was found in all animals regardless of whether diarrhea was present. In addition, the upregulation of interleukin-1 alpha (IL-1 alpha), IL-3, and tumor necrosis factor alpha cytokine genes, accompanied by an increased presence of activated (CD4(+) CD69(+)) T lymphocytes was found in gut-associated lymphoid tissues collected from animals with chronic enterocolitis and diarrhea in comparison with clinically healthy controls (P < 0.05). These data indicate that chronic enterocolitis and diarrhea are associated, in part, with a variety of enteric pathogens and highlight the importance of defining the microbiological status of nonhuman primates used for infectious disease studies. The data also suggest that chronic colitis in rhesus macaques may have potential as a model of inflammatory bowel disease in humans.

Animals↗