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PubMed2002

Comparative and evolutionary analysis of the rhesus macaque extended MHC class II region.

The sequence-based map of a part of the rhesus macaque major histocompatibility complex (MHC) extended class II region is presented. The sequenced region encompasses 67,401 bp and contains the SACM2L, RING1, FABGL and KE4 genes, as well as the HTATSF1-like and ZNF-like pseudogenes. Similar to human, but different from rat and mouse, no class I genes are found in the SACM2L- RING1 interval. The rhesus macaque extended MHC class II region shows a high degree of conservation of exonic as well as intronic and intergenic sequences compared with the respective human region. It is concluded that this particular genomic organization of the extended class II region-i.e., the absence of class I genes and the presence of the HTATSF1-like and ZNF-like pseudogenes-can be traced back to a common ancestor of humans and rhesus macaques about 23 million years ago.

Animals↗

PubMed2001

Intraspecies heterogeneity of immunoglobulin alpha-chain constant region genes in rhesus macaques.

Immunoglobulin A (IgA) is the major antibody class present in external secretions and is also an important component of serum immunoglobulins. On mucosal surfaces, IgA represents a first line of defence by neutralizing invading pathogens. The number of IgA constant-region genes (C alpha) present in different mammalian species is variable. Immunoglobulin C alpha genes differ mainly in the sequences located in the hinge region. IgA molecules, whose hinge regions are remarkably similar to those of the respective human molecules, are present in hominoid primates. In this report, we show that two alleles of a single immunoglobulin C alpha are present in rhesus macaques (Macaca mulatta). In addition, we show that intraspecies immunoglobulin C alpha allelic polymorphism is very high in this non-human primate species. Specifically, five different hinge regions, some of which are proline-rich, were identified from a total of eight rhesus macaque immunoglobulin C alpha-chains. The five hinge regions were different from those present in hominoid primates, both in length and in sequence. These results represent the first example of high levels of intraspecies immunoglobulin constant-region variability and suggest that IgAs of variable structure and function may be present in rhesus macaques. As rhesus macaques are widely used as animal models for the development of vaccines for acquired immune deficiency syndrome (AIDS), the possible presence of structurally and functionally variable IgA molecules in different animals should be taken into account when designing experimental strategies to induce mucosal antibody responses to human immunodeficiency virus (HIV).

Alleles↗

PubMed1999

Skeletal survey of Cayo Santiago rhesus macaques: osteoarthritis and articular plate excrescences.

OBJECTIVES: This study was performed to complement studies on spondyloarthropathy in rhesus macaques by quantifying and characterizing another major form of arthritis and contrasting it with osteoarthritis. METHODS: Skeletons of 269 macaques of known age and troop affiliation from the free-ranging Cayo Santiago colony (Caribbean Primate Research Center) were macroscopically surveyed for the presence of articular changes of osteoarthritis, articular plate excrescences, and calcifications that project back over the joint surface in all diarthrodial joints. Statistical tests were used to establish the independence of pathological conditions, age, gender, troop membership, and specific joint involvement. RESULTS: Subchondral articular surface excrescences or calcific plate-like articular surface overgrowth were noted in 17% and osteoarthritis in 18% of Cayo Santiago macaques. Distribution of joint involvement and sex ratio (1:1) of the former condition were independent of either troop membership or the distribution of osteoarthritis. CONCLUSION: Three major forms of arthritis are common in rhesus macaques: osteoarthritis, spondyloarthropathy, and a category that might be referred to as apical plate excrescences (APE). The latter is very different from spondyloarthropathy, rheumatoid arthritis, osteoarthritis, gout, and infectious arthritis. It is quite similar to what in the past has been referred to as the radiographic form of calcium pyrophosphate deposition disease (CPPD) in humans. A new name has not been offered for the identification/categorization of this phenomenon in dry bone. Its occurrence in rhesus macaques appears to present a natural model for characterization of genetic, immunologic, and environmental aspects of this phenomenon. The acronym APE is offered for consideration in naming this category of arthritis in skeletal material.

Animals↗

PubMed2001

Toward developing a genome-wide microsatellite marker set for linkage analysis in the rhesus macaque (Macaca mulatta): identification of 76 polymorphic markers.

Linkage analysis can be problematic in humans because of the lack of large, multigenerational pedigrees and the difficulties in obtaining phenotypic data on all family members. In contrast, large, captive colonies of rhesus macaque are a potentially valuable resource for linkage studies because detailed phenotypic and genealogical data are kept, inbreeding is avoided, and DNA samples can usually be obtained. Microsatellite marker sets for genome-wide screening are available in a number of species, but not for the rhesus macaque. We tested primers to 400 human microsatellite markers from a genome-wide mapping set using DNA from nine unrelated female rhesus macaques. We found that 76 (19%) of the primers amplified a polymorphic product using the standard protocols for human DNA. The average heterozygosity of the markers in humans was 0.80, compared to 0.65 in the rhesus macaques. This study provides preliminary data, which could be used toward the development of a linkage mapping set in this species. There would be a need, however, to confirm the Mendelian inheritance of the markers.

Animals↗

PubMed2001

High-efficiency gene transfer into rhesus macaque primary T lymphocytes by combining 32 degrees C centrifugation and CH-296-coated plates: effect of gene transfer protocol on T cell homing receptor expression.

Although steady progress has been made in transducing human T lymphocytes by Moloney murine leukemia virus (Mo-MuLV)-based vectors, few studies have been done to define ex vivo gene transfer protocols to transduce rhesus macaque primary T lymphocytes. Given the fact that simian immunodeficiency virus (SIV) infection in rhesus macaque is a well-characterized model for human immunodeficiency virus (HIV), it is of great interest to develop an efficient protocol to transduce rhesus macaque primary T cells. In this study, we have used MuLV-10A1-pseudotyped retrovirus expressing enhanced green fluorescent protein (EGFP) to evaluate a number of ex vivo gene transfer protocols in rhesus macaque primary T lymphocytes. Our objectives in designing these protocols were (1) to test whether higher efficiency gene transfer could be obtained by combining two previously defined protocols, centrifugation at 32 degrees C and the CH-296-coated plate; and (2) to study the effect of an ex vivo gene transfer protocol on the expression of lymphocyte homing receptors L-selectin and alpha 4 beta 7 and alpha 4 beta 1 integrins. From seven independent experiments we demonstrate by flow cytometry analyses of EGFP expression that whereas centrifugation at 32 degrees C or the fibronectin fragment CH-296-coated plate protocol alone yielded 10-14% transduction efficiency, combining these two protocols resulted in 28.1-51.2% transduction efficiency. EGFP in transduced cells was expressed highly throughout the 14 days of posttransduction expansion. Our results also demonstrate that whereas the transduction procedure per se did not significantly alter the expression of lymphocyte homing receptors, anti-CD3 and anti-CD28 antibody stimulation profoundly reduced the expression of L-selectin. The selective reduction of L-selectin may result in significant in vivo consequences if transduced cells are infused.

Animals↗

PubMed1994

Intravaginal inoculation of rhesus macaques with cell-free simian immunodeficiency virus results in persistent or transient viremia.

The simian immunodeficiency virus (SIV)-rhesus macaque model of heterosexual human immunodeficiency virus transmission consists of atraumatic application of cell-free SIVmac onto the intact vaginal mucosa of mature female rhesus macaques. This procedure results in systemic infection, and eventually infected animals develop the clinical signs and pathologic changes of simian AIDS. To achieve 100% transmission with the virus stocks used to date, multiple intravaginal inoculations are required. The current titration study utilized two stocks of SIVmac and demonstrated that a single intravaginal dose of cell-free SIV can reliably produce infection in rhesus macaques. This study also demonstrated that some animals intravaginally inoculated with cell-free SIVmac develop transient viremia characterized by a limited ability to isolate virus from peripheral blood mononuclear cells and lymph node mononuclear cells and no seroconversion to SIV antigen. SIV could be isolated from the peripheral lymph nodes of transiently viremic animals only during periods of viremia and not at times when SIV was not detected in circulating mononuclear cells. Thus, peripheral lymphoid tissues were not reservoirs of infection in the transiently viremic animals. Taken together, these results suggest either that the SIV infection was cleared in the transiently viremic animals or that SIV infection is limited to a compartment of the genital mucosal immune system that cannot be assessed by monitoring SIV infection in peripheral blood mononuclear cells and peripheral lymphoid tissue.

Animals↗

PubMed2000

Food-neophobia in semi-free ranging rhesus macaques: effects of food limitation and food source.

This study characterizes food neophobia in semi-free ranging rhesus macaques. In experiment one, monkeys received novel and familiar foods during periods of normal provisioning and when provisioning was suspended. The monkeys did discriminate between novel and familiar foods and continued to exhibit neophobia when provisioning was suspended. In experiment two, food was either tossed to subjects or placed in the habitat so that monkeys discovered food without the observer in close proximity. Rhesus macaques were more likely to eat a novel food that was hand-tossed to them compared to food they discovered in their habitat. This study suggests that food neophobia is a robust trait in rhesus macaques and that a history of provisioning may affect the expression of the trait.

Animal Feed↗

PubMed1993

Differences in the B and T cell immune response to the envelope glycoprotein 130 (gp130) of the macaque strain of simian immunodeficiency virus (SIVmac), induced by immunization of rhesus macaques with virus-derived or vaccinia virus-expressed gp130.

Rhesus macaques were immunized with purified virus-derived simian immunodeficiency virus of macaques (SIVmac) 251/32H glycoprotein 130 (gp130) or primed with recombinant vaccinia virus (VV) expressing the env gene of the SIVmac BK28 clone and boosted subsequently with virus-derived gp130. High antibody titres of at least 10(4) against recombinant gp140 were induced with both vaccines. Analysis of the antibody specificity with a peptide ELISA revealed that different linear epitopes were recognized after administration of virus-derived gp130 compared with those after priming with VV. Antibodies to some epitopes (peptides 10 and 49), which were also found in SIV-infected animals, were induced with both vaccines, whereas antibodies to other regions were induced by only one vaccine preparation. The analysis of the helper T cell response revealed a poor immunogenicity of the virus-derived gp130, whereas priming with VV induced a considerable helper T cell activity in all three vaccinees after the second VV infection. Using synthetic peptides, several epitopes were identified. Our observations show that immunization with a virus-derived gp130 or live recombinant VV induces a considerably different antibody and helper T cell response. These differences in immunogenicity might have important implications for further vaccine development.

Amino Acid Sequence↗

PubMed1985

Compensated, goitrous hypothyroidism in rhesus macaques.

Bilateral cervical masses were observed in two newborn, male, rhesus macaques. The clinical diagnosis was congenital goiter. Thyroid function screening tests revealed that the affected monkeys had normal triiodothyronine levels, low thyroxine values, and elevated thyroid-stimulating hormone levels. Radioactive iodine uptake and perchlorate discharge tests indicated a postorganification defect. A third, male, rhesus macaque, stillborn after a prolonged gestation, also had bilateral cervical masses. Necropsy and histopathology examinations confirmed the masses were enlarged, hyperplastic thyroid glands. Each affected infant had the same parents.

Animals↗

PubMed1998

Localization of Simian immunodeficiency virus-infected cells in the genital tract of male and female Rhesus macaques.

The SIV/Rhesus macaque model of HIV transmission has led to an increased understanding of the interactions between virus and host during the sexual transmission of HIV. SIV can be transmitted across the intact mucosa (stratified squamous epithelium) of the foreskin and glans of the penis of Rhesus macaques. SIV-infected cells can be found at all levels of the male Rhesus macaque reproductive tract and SIV can infect cells in the mucosal epithelium of the foreskin of the penis. SIV can be transmitted to female Rhesus macaques by infusing a cell-free virus suspension into the vaginal canal through a soft plastic pediatric nasogastric feeding tube. There does not appear to be any correlation between inoculation at any particular point in the menstrual cycle and the susceptibility of an animal to infection. Furthermore, the surgical removal of the cervix and uterus did not affect the dose of cell-free virus required for the genital transmission of SIV. Thus, target cells for SIV are present in the vaginal mucosa. In chronically-infected female Rhesus macaques, SIV-infected cells are present in the uterus, cervix and vagina. SIV-infected CD1a+ and p55+ Langerhans cells are also found within the stratified squamous epithelium of the vagina. Taken together these results are consistent with the hypothesis that the virus initially infects antigen-presenting cells in the vagina (macrophages and Langerhans cells) and then subsequent rounds of replication occur in the draining lymph nodes prior to spreading to more proximal lymphoid nodes and finally to the bloodstream and distant lymphoid tissue.

Animals↗

PubMed1999

Motor skill impairment in SIV-infected rhesus macaques with rapidly and slowly progressing disease.

A number of studies have shown that simian immunodeficiency virus (SIV) infection in rhesus macaques parallels many aspects of HIV disease in humans. The purpose of this study was to further characterize the rhesus macaque infected with neurovirulent SIV as a model of neuroAIDS. Using a motor skill task, our objective was to detect SIV-related movement impairments in behaviorally trained macaques. The motor skill task required retrieval of a food pellet from a cup in a rotating turntable across a range of speeds. Nine monkeys were infected with neurovirulent strains of SIVmac (R71/17E): four monkeys served initially as controls pre-inoculation. Seven monkeys developed simian AIDS within 4 months of inoculation (rapid progressors), and two survived more than 18 months post-inoculation (slow progressors). Of the rapid progressors, five exhibited significant deficits in this task, most showing a gradual decline in performance terminating in a sharp drop to severely impaired levels of performance. One slow progressor (AQ15) showed no performance declines. The other slow progressor (AQ94) showed a significant decrease in maximum speed that was concurrent with the onset of clinical signs. For AQ94, the role of sickness behavior related to late stage simian AIDS could not be ruled out. These results demonstrate that motor system impairment can be detected early in the course of SIV infection in rhesus macaques, further establishing the SIVmac-infected macaque monkey as a viable model of neuroAIDS.

Animals↗

PubMed2002

Molecular cloning and sequencing of 25 different rhesus macaque chemokine cDNAs reveals evolutionary conservation among C, CC, CXC, AND CX3C families of chemokines.

Chemokines are small chemoattractant cytokines involved in normal and pathological immune processes. Although extensive nucleotide sequence data are available for human and murine chemokine cDNA sequences, very few data are currently available regarding rhesus macaque sequences. To increase our understanding of immune function in nonhuman primates, we have used reverse-transcription polymerase chain reaction (RT-PCR) to clone and sequence rhesus macaque cDNAs from each of the C, CC, CXC, and CX3C groups of chemokines. Relative to the respective human chemokines, these 25 chemokine cDNA sequences were from 77% to 98% identical. Of the amino acid differences between the rhesus macaque and human chemokines, 51% were species-specific when compared together with the respective murine chemokine sequences. These studies of rhesus macaque chemokine sequences demonstrate that chemokine genes are highly conserved across species, and provide a large foundation for the study of chemokine biology and genetics in nonhuman primates.

Amino Acid Sequence↗

PubMed2005

Combined-type osteosarcoma in a rhesus macaque.

A femoral mass from a 15-year-old rhesus macaque was evaluated. Grossly, the mass consisted of a large, osteolytic focus in the distal femur, a gelatinous core of neoplastic tissue in the medullary cavity, and an invasive mass-obliterating musculature of the thigh. On histopathologic evaluation, three neoplastic mesenchymal cell populations, osteoblasts, fibroblasts, and primitive mesenchymal cells were identified. The mass was diagnosed as a combined type osteosarcoma. To our knowledge, this is the first osteosarcoma in a rhesus macaque with this subclassification.

Amputation, Surgical↗

PubMed2005

Complex assembly, crystallization and preliminary X-ray crystallographic studies of rhesus macaque MHC Mamu-A*01 complexed with an immunodominant SIV-Gag nonapeptide.

Simian immunodeficiency virus (SIV) infection in rhesus macaques has been used as the best model for the study of human immunodeficiency virus (HIV) infection in humans, especially in the cytotoxic T-lymphocyte (CTL) response. However, the structure of rhesus macaque (or any other monkey model) major histocompatibility complex class I (MHC I) presenting a specific peptide (the ligand for CTL) has not yet been elucidated. Here, using in vitro refolding, the preparation of the complex of the rhesus macaque MHC I allele (Mamu-A*01) with human beta2m and an immunodominant peptide, CTPYDINQM (Gag_CM9), derived from SIV Gag protein is reported. The complex (45 kDa) was crystallized; the crystal belongs to space group I422, with unit-cell parameters a = b = 183.8, c = 155.2 A. The crystal contains two molecules in the asymmetric unit and diffracts X-rays to 2.8 A resolution. The structure is being solved by molecular replacement and this is the first attempt to determined the crystal structure of a peptide-nonhuman primate MHC complex.

Amino Acid Sequence↗

PubMed2003

Genetic variation at the mitochondrial large-subunit rRNA locus of Pneumocystis isolates from simian immunodeficiency virus-infected rhesus macaques.

The nucleotide sequences of a segment of the Pneumocystis mitochondrial large-subunit (mt LSU) rRNA gene from rhesus macaques coinfected with simian immunodeficiency virus (SIV) and Pneumocystis carinii were examined. Of 12 isolates examined, 3 were found to be identical and the others showed substantial sequence variation, with up to 13% divergence among variants. We identified two general sequence types that differed at several sites, including a conserved 26-nucleotide insertion. Four monkeys had evidence of two Pneumocystis variants present simultaneously, indicative of a mixed infection. There was a high degree of variance between the rhesus macaque-derived Pneumocystis mt LSU rRNA gene sequence and the cognate sequences in Pneumocystis organisms derived from other hosts. Analysis of the mt LSU rRNA genes of Pneumocystis organisms derived from rhesus macaques and several other mammalian hosts supports the observation that rhesus macaque-derived Pneumocystis is most closely related to human-derived PNEUMOCYSTIS: In addition, the data identify the mt LSU rRNA gene as an informative locus for transmission and epidemiological studies of the SIV-rhesus macaque model of Pneumocystis infection.

Animals↗

PubMed2001

Identification of the rhesus macaque rhadinovirus lytic origin of DNA replication.

We have identified a lytic origin of DNA replication (oriLyt) for rhesus macaque rhadinovirus (RRV), the rhesus macaque homolog of human herpesvirus 8 (HHV-8), also known as Kaposi's sarcoma-associated herpesvirus. RRV oriLyt maps to the region of the genome between open reading frame 69 (ORF69) and ORF71 (vFLIP) and is composed of an upstream A+T-rich region followed by a short (300-bp) downstream G+C-rich DNA sequence. A set of overlapping cosmids corresponding to the entire genome of RRV was capable of complementing oriLyt-dependent DNA replication only when additional ORF50 was supplied as an expression plasmid in the transfection mixture, suggesting that the level of ORF50 protein originating from input cosmid DNA was insufficient. The requirement of RRV ORF50 in the cotransfection replication assay may also suggest a direct role for this protein in DNA replication. RRV oriLyt shares a high degree of nucleotide sequence and G+C base distribution with the corresponding loci in HHV-8.

Animals↗

PubMed1995

Early intrathecal events in rhesus macaques (Macaca mulatta) infected with pathogenic or nonpathogenic molecular clones of simian immunodeficiency virus.

BACKGROUND: Encephalitis is a common and devastating sequela of HIV infection in humans and of simian immunodeficiency virus (SIV) infection in rhesus macaques. We used the SIV-infected rhesus macaque model to study early intrathecal events in the pathogenesis of lentiviral encephalitis. EXPERIMENTAL DESIGN: To examine early events and to compare the neuroinvasiveness and neurovirulence of pathogenic (SIVmac239) and nonpathogenic (SIVmac1A11) molecular clones of SIV and the role of host immunity in the early postinfection period, we inoculated groups of rhesus macaques with each of these clones and compared them with a third group of animals inoculated with pathogenic uncloned SIV (SIVmac). We collected paired cerebrospinal fluid and sera before and at intervals after inoculation and determined albumin and IgG concentrations, SIV-specific humoral immune response, and concentrations of quinolinic acid. Two animals from each group were killed and necropsied at 2, 8, 13, and 23 weeks after inoculation. Routine histopathology and semi-quantitative in situ hybridization were performed on tissue from multiple levels of the central nervous system (CNS). RESULTS: SIVmac and SIVmac-239 invaded both the meninges and the CNS parenchyma simultaneously within 2 weeks of inoculation, whereas nonpathogenic SIVmac-1A11 was not neuroinvasive. Gross disruption of the blood-brain barrier was not detected at any time. However, elevated IgG indices and high levels of cerebrospinal fluid quinolinic acid denoted intrathecal immune activation soon after viral neuroinvasion. Virus load in the CNS declined as the immune response peaked but subsequently increased with waning immunity. One macaque that never developed an SIV-specific immune response died with severe SIV encephalitis. CONCLUSIONS: Our findings support the following hypotheses of early events in SIV neuropathogenesis: (a) Pathogenic virus invades the CNS within days of i.v. inoculation and elicits an intrathecal immune response, including intrathecal synthesis of IgG and macrophage activation; (b) the immune response initially is associated with a decreased virus load in the CNS; (c) as immunodeficiency develops, virus load in the CNS increases once again; and (d) both virus and host factors are important in determining the course of events.

Animals↗

PubMed2004

Physiological predictors of reproductive outcome and mother-infant behaviors in captive rhesus macaque females (Macaca mulatta).

Previous research has shown that offspring of females with low cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) concentrations are less likely to survive the first year of life than are offspring of females with high CSF 5-HIAA concentrations. In addition, studies of free-ranging rhesus macaque males have suggested that individuals with low CSF 5-HIAA concentrations suffer reduced reproductive success relative to their high serotonin counterparts. We examined CSF concentrations of the monoamine metabolites 5-HIAA and homovanillic acid (HVA), and plasma cortisol concentrations as predictors of first-time adult reproductive potential, maternal behavior, and overall social interactions in two groups of captive female rhesus macaques and their first offspring. Repeated CSF and blood samples were obtained from adult females in two social groups, and focal observations were performed for both new mothers and infants during the first month following parturition. We found that the reproductively aged nulliparous females who failed to give birth to their first offspring showed significantly lower CSF 5-HIAA concentrations than those females who gave birth. Among those females that gave birth to offspring, females with low CSF 5-HIAA concentrations and females with high plasma cortisol concentrations were overly protective and restrictive with their infants. CSF HVA concentration was not associated with reproductive output, social behavior, aggression, or mother-infant interactions in this sample of rhesus macaque females. We conclude that low CNS serotonin activity and high stress, measured by high plasma cortisol, are correlated with reduced reproductive success and patterns of high maternal restrictiveness in young adult female rhesus macaques.

Aggression↗