Indian-origin Rhesus Macaques Research Articles

Reproductive efficiency of captive Chinese- and Indian-origin rhesus macaque (Macaca mulatta) females.

Reproductive and survival records (n=2,913) from 313 Chinese-origin and 365 Indian-derived rhesus macaques at the Tulane National Primate Research Center (TNPRC) spanning three generations were studied. Least-squares analysis of variance procedures were used to compare reproductive and infant survival traits while proportional hazards regression procedures were used to study female age at death, number of infants born per female, and time from last birth to death. Chinese females were older at first parturition than Indian females because they were older when placed with males, but the two subspecies had similar first postpartum birth interval (1st PPBI) and lifetime postpartum birth interval (LPPBI). Females that gave birth to stillborn infants had shorter first postpartum birth intervals (1st PPBI) than females giving birth to live infants. Postpartum birth intervals decreased in females from age 3 to 12 but then increased again with advancing age. Chinese infants had a greater survival rate than Indian infants at 30 days, 6 months, and 1 year of age. Five hundred and forty-three females (80.01%) had uncensored, or true records for age at death, number of infants born per female, and time from the birth until death whereas 135 females (19.91%) had censored records for these traits. Low- and high-uncensored observations for age at death were 3 and 26 years for Chinese, and 3 and 23 years for Indian females. Uncensored number of infants born per female ranged from 1 to 15 for Chinese females and 1 to 18 for Indian females. Each of these traits was significantly influenced by the origin×generation interaction in the proportional hazards regression analyses, indicating that probabilities associated with age at death, number of infants born per female, and time from last birth to death for Chinese and Indian females did not rank the same across generations.

Chromobacterium violaceum infections in 13 non‐human primates

Recently, an Indian-origin macaque was found dead and Chromobacterium violaceum was isolated from the skin wound, and hepatic and pulmonary abscesses. By searching the database, a total of thirteen cases of C. violaceum infection in pigtail macaques (n = 8), rhesus macaques (n = 4), and one baboon were identified from 2001 to 2010 at Tulane National Primate Research Center. Medical records were reviewed for breed, sex, age, clinical findings, treatment, outcome, bacteriology, and gross and histological findings. Seven pigtail macaques and one Indian-origin rhesus macaque died of chromobacterial septicemia. All chromobacterial septicemic pigtail macaques were adult with higher incidence in female. Hepatic abscess and thrombosis were typical findings along with pulmonary abscess and thrombosis, renal venous thromboembolism, and necrosuppurative pleuritis, peritonitis, splenitis, myocarditis, pericarditis, and meningoencephalitis. Skin wound, uterine infection, and oral and respiratory exposure were considered the points of entry for these animals. This represents the first report of chromobacteriosis in pigtail, rhesus macaque, and baboon. Our experience suggests that chromobacterial infections may be more common in non-human primates than previously recognized.

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

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.

TRIM5 allelic polymorphism in macaque species/populations of different geographic origins: its impact on SIV vaccine studies

Tripartite motif 5α (TRIM5α) is a potent antiretroviral immune factor present in the cytoplasm of cells of most tissue types. The rhesus macaque TRIM5 gene has been shown to display polymorphism, with different variants being divided into three groups (TRIM5(TFP), TRIM5(Q), and TRIM5(CypA)), which may have divergent retroviral effects on infection. Along with rhesus macaques, cynomolgus macaques are also used in simian immunodeficiency virus (SIV) infection studies. As a consequence, TRIM5 genotyping of these animals will contribute to interpreting the outcome of such studies. The present communication covers Burmese, Chinese, and a large cohort of Indian-origin rhesus macaques, and describes the first large cohort study on TRIM5 polymorphism in outbred cynomolgus macaques. We demonstrate the presence of the TRIM5(TFP) group in cynomolgus macaques. In addition, we have re-evaluated historical samples of rhesus macaques challenged with SIV(mac251), a virus that has been reported to be partially suppressed by particular rhesus macaque TRIM5 variants.

SIV-infected Chinese-origin rhesus macaques express specific MHC class I alleles in either elite controllers or normal progressors

SIV-infected Chinese-origin rhesus macaques express specific MHC class I alleles in either elite controllers or normal progressors

The role of MHC class I allele Mamu-A*07 during SIV(mac)239 infection.

Virus-specific CD8(+) T cells play an important role in controlling HIV/SIV replication. These T cells recognize intracellular pathogen-derived peptides displayed on the cell surface by individual MHC class I molecules. In the SIV-infected rhesus macaque model, five Mamu class I alleles have been thoroughly characterized with regard to peptide binding, and a sixth was shown to be uninvolved. In this study, we describe the peptide binding of Mamu-A1*007:01 (formerly Mamu-A*07), an allele present in roughly 5.08% of Indian-origin rhesus macaques (n = 63 of 1,240). We determined a preliminary binding motif by eluting and sequencing endogenously bound ligands. Subsequently, we used a positional scanning combinatorial library and panels of single amino acid substitution analogs to further characterize peptide binding of this allele and derive a quantitative motif. Using this motif, we selected and tested 200 peptides derived from SIV(mac)239 for their capacity to bind Mamu-A1*007:01; 33 were found to bind with an affinity of 500nM or better. We then used PBMC from SIV-infected or vaccinated but uninfected, A1*007:01-positive rhesus macaques in IFN-γ Elispot assays to screen the peptides for T-cell reactivity. In all, 11 of the peptides elicited IFN-γ(+) T-cell responses. Six represent novel A1*007:01-restricted epitopes. Furthermore, both Sanger and ultradeep pyrosequencing demonstrated the accumulation of amino acid substitutions within four of these six regions, suggestive of selective pressure on the virus by antigen-specific CD8(+) T cells. Thus, it appears that Mamu-A1*007:01 presents SIV-derived peptides to antigen-specific CD8(+) T cells and is part of the immune response to SIV(mac)239.

Characterization of single-nucleotide variation in Indian-origin rhesus macaques (Macaca mulatta)

BackgroundRhesus macaques are the most widely utilized nonhuman primate model in biomedical research. Previous efforts have validated fewer than 900 single nucleotide polymorphisms (SNPs) in this species, which limits opportunities for genetic studies related to health and disease. Extensive information about SNPs and other genetic variation in rhesus macaques would facilitate valuable genetic analyses, as well as provide markers for genome-wide linkage analysis and the genetic management of captive breeding colonies.ResultsWe used the available rhesus macaque draft genome sequence, new sequence data from unrelated individuals and existing published sequence data to create a genome-wide SNP resource for Indian-origin rhesus monkeys. The original reference animal and two additional Indian-origin individuals were resequenced to low coverage using SOLiD™ sequencing. We then used three strategies to validate SNPs: comparison of potential SNPs found in the same individual using two different sequencing chemistries, and comparison of potential SNPs in different individuals identified with either the same or different sequencing chemistries. Our approach validated approximately 3 million SNPs distributed across the genome. Preliminary analysis of SNP annotations suggests that a substantial number of these macaque SNPs may have functional effects. More than 700 non-synonymous SNPs were scored by Polyphen-2 as either possibly or probably damaging to protein function and these variants now constitute potential models for studying functional genetic variation relevant to human physiology and disease.ConclusionsResequencing of a small number of animals identified greater than 3 million SNPs. This provides a significant new information resource for rhesus macaques, an important research animal. The data also suggests that overall genetic variation is high in this species. We identified many potentially damaging non-synonymous coding SNPs, providing new opportunities to identify rhesus models for human disease.

Microsatellite Instability in Rhesus Colon Carcinoma

Twenty‐five colon carcinoma cases from a specific pathogen free (SPF) breeding colony of Indian origin rhesus macaques (Macaca mulatta) were examined and evaluated for pathogenesis. Although, no specific mode of inheritance was identified there appeared to be a genetic bias, as several parent‐offspring or sibling‐sibling pairs were identified. In a subset of cases, DNA from the tumors and normal tissues from the same animal and tested for microsatellite instability (MSI) utilizing a panel of rhesus dinucleotides (MML3S7, MML4S1, MML11S1, MML16S3, MML17S1, MML17S2 and MML18S3) and a human mononucleotide (BAT‐25). All tumors tested exhibited some degree of microsatellite instability. Immunohistochemistical staining for mutL homolog 1 (MLH1), mutS homolog 2 (MSH2) and mutS homolog 6 (MSH6) was performed with loss of MLH1 staining being observed in several tumors. Rhesus colon carcinoma in the Bastrop colony with its early onset disease, microsatellite instability and loss of MLH1 may represent model of Lynch syndrome.

Vaccine-induced T cells Provide Partial Protection Against High-dose Rectal SIVmac239 Challenge of Rhesus Macaques

Despite enormous efforts by the scientific community, an effective HIV vaccine remains elusive. To further address to what degree T cells in absence of antibodies may protect against simian immunodeficiency virus (SIV) disease progression, rhesus macaques were vaccinated intramuscularly with a chimpanzee-derived Ad vector (AdC) serotype 6 and then boosted intramuscularly with a serologically distinct AdC vector of serotype 7 both expressing Gag of SIVmac239. Animals were subsequently boosted intramuscularly with a modified vaccinia Ankara (MVA) virus expressing Gag and Tat of the homologous SIV before mucosal challenge with a high dose of SIVmac239 given rectally. Whereas vaccinated animals showed only a modest reduction of viral loads, their overall survival was improved, in association with a substantial protection from the loss of CD4(+) T cells. In addition, the two vaccinated Mamu-A*01(+) macaques controlled viral loads to levels below detection within weeks after challenge. These data strongly suggest that T cells, while unable to affect SIV acquisition upon high-dose rectal infection, can reduce disease progression. Induction of potent T-cell responses should thus remain a component of our efforts to develop an efficacious vaccine to HIV-1.

X Chromosomal Variation Is Associated with Slow Progression to AIDS in HIV-1-Infected Women

AIDS has changed from a mostly male-specific health problem to one that predominantly affects females. Although sex differences in HIV-1 susceptibility are beyond doubt, the extent to which sex affects the onset and progression of AIDS has remained elusive. Here, we provide evidence for an influence of X chromosomal variation on the course of retroviral infection, both in HIV-1-infected patients and in the rhesus macaque model of AIDS. A two-stage, microsatellite-based GWAS of SIV-infected monkeys revealed MHC class I markers and a hitherto-unknown X chromosomal locus as being associated with a nominal score measuring progression to AIDS (Fisher's exact p < 10(-6)). The X chromosomal association was subsequently confirmed in HIV-1-infected patients with published SNP genotype data. SNP rs5968255, located at human Xq21.1 in a conserved sequence element near the RPS6KA6 and CYLC1 genes, was identified as a significant genetic determinant of disease progression in females (ANOVA p = 8.8 x 10(-5)), but not in males (p = 0.19). Heterozygous female carriers of the C allele showed significantly slower CD4 cell decline and a lower viral load at set point than TT homozygous females and than males. Inspection of HapMap revealed that the CT genotype is significantly more frequent among Asians than among Europeans or Africans. Our results suggest that, in addition to the individual innate and adaptive immunity status, sex-linked genetic variation impacts upon the rate of progression to AIDS. Elucidating the mechanisms underlying this sex-specific effect will promote the development of antiretroviral therapies with high efficacy in both sexes.

Evidence for balancing selection acting on KIR2DL4 genotypes in rhesus macaques of Indian origin

The interaction of killer-cell immunoglobulin-like receptors (KIR) and their respective major histocompatibility complex (MHC) ligands can alter the activation state of the natural killer (NK) cell. In both humans and rhesus macaques, particular types of non-classical MHC class I molecules are predominantly expressed on the trophoblast. In humans, human leukocyte antigen G has been demonstrated to act as a ligand for KIR2DL4, present on all NK cells, whereas Mamu-AG may execute a similar function in rhesus macaques. During primate evolution, orthologues of KIR2DL4 appear to have been highly conserved, suggesting strong purifying selection. A cohort of 112 related and unrelated rhesus macaques of mostly Indian origin were selected to study their KIR2DL4 genes for the occurrence of polymorphism. Comparison of the proximal region provided evidence for strong conservative selection acting on the exons encoding the Ig domains. As is found in humans, in the Indian rhesus macaque population, two different KIR2DL4 entities are encountered, which differ for their intra-cellular signalling motifs. One genotype contains a complex mutation in the distal region of exon 9, which negates a serine/threonine kinase site. Furthermore, both allelic entities are present in a distribution, which suggests that balancing selection is operating on these two distinct forms of KIR2DL4.

Functional variation in the 3′ untranslated region of the serotonin transporter in human and rhesus macaque

The serotonin system underlies a wide variety of behavioral traits and its dysregulation is the cause of numerous neuropsychiatric disorders. Among genes involved in the system, the serotonin transporter (SERT) is integral and has been repeatedly shown to be associated with disease as well as being a primary drug target. In addition to promoter region variation, we identify here variation in a regulatory region in the 3' untranslated region (UTR) of the SERT gene in both humans and rhesus macaques. We comprehensively survey the 3' UTR of SLC6A4 in Indian-origin rhesus macaques to identify three single nucleotide polymorphisms (SNPs) creating two haplotypes, both derived from an ancestral sequence, that represent the vast majority of the alleles in the population. Through the use of a luciferase reporter gene assay, we are able to show that not only do these alleles have differential effects on gene expression, modulated through changes in messenger RNA stability, but that different commonly occurring SNPs in the human 3' UTR also have similar effects. This finding not only offers additional insight into the regulation, and thus dysregulation, of SERT expression, but also suggests the role of natural selection in maintaining both high and low SERT expression levels broadly across populations of multiple primate species.

Human Expression Variation in the Mu-Opioid Receptor is Paralleled in Rhesus Macaque

The mu-opioid receptor is a key component in many neurobiological systems including those affecting perceptions of pain and pleasure. In humans and non-human primate model systems, genetic variation in the receptor has been associated with numerous behavioral and physiological traits. In humans, polymorphisms have been identified which affect not only the biochemical function of the receptor, but also expression level. Existing rhesus macaque variation parallels the functional protein changes seen in human, but it remains unknown if expression level differences or concomitant protein changes may also exist. Here we perform a comprehensive survey of naturally occurring polymorphisms in Indian-origin rhesus macaques and identify three 5' UTR haplotypes with effects on expression level. These expression level effects are in linkage disequilibrium with the previously identified rhesus coding polymorphism C77G. The C77G polymorphism in rhesus parallels the functional effects of the A118G polymorphism in humans and expression level differences occur within both species. Together, the functional variations reported here have implications for future studies seeking to model the opioid system and its associated phenotypes in rhesus macaques.

CD163, a Marker of Perivascular Macrophages, Is Up-Regulated by Microglia in Simian Immunodeficiency Virus Encephalitis after Haptoglobin-Hemoglobin Complex Stimulation and Is Suggestive of Breakdown of the Blood-Brain Barrier

Macrophages and microglia are the major cell types infected by human immunodeficiency virus and simian immunodeficiency virus (SIV) in the central nervous system. Microglia are likely infected in vivo, but evidence of widespread productive infection (ie, presence of viral RNA and protein) is lacking. This conclusion is controversial because, unlike lymphocytes, macrophages and microglia cannot be discreetly immunophenotyped. Of particular interest in the search for additional monocyte/macrophage-lineage cell markers is CD163; this receptor for haptoglobin-hemoglobin (Hp-Hb) complex, which forms in plasma following erythrolysis, is expressed exclusively on cells of monocyte/macrophage lineage. We examined CD163 expression in vitro and in vivo by multiple techniques and at varying times after SIV infection in macaques with or without encephalitis. In normal and acutely SIV-infected animals, and in SIV-infected animals without encephalitis, CD163 expression was detected in cells of monocyte/macrophage lineage, including perivascular macrophages, but not in parenchymal microglia. However, in chronically infected animals with encephalitis, CD163 expression was detected in activated microglia surrounding SIV encephalitis lesions in the presence of Hp-Hb complex, suggesting leakage of the blood-brain barrier. CD163 expression was also induced on microglia in vitro after stimulation with Hp-Hb complex. We conclude that CD163 is a selective marker of perivascular macrophages in normal macaques and during the early phases of SIV infection; however, later in infection in animals with encephalitis, CD163 is also expressed by microglia, which are probably activated as a result of vascular compromise.

Selective induction of cell-mediated immunity and protection of rhesus macaques from chronic SHIV KU2 infection by prophylactic vaccination with a conserved HIV-1 envelope peptide-cocktail

Infection of Indian-origin rhesus macaques by the simian human immunodeficiency virus (SHIV) is considered to be a suitable preclinical model for directly testing efficacy of vaccine candidates based on the HIV-1 envelope. We used this model for prophylactic vaccination with a peptide-cocktail comprised of highly conserved HIV-1 envelope sequences immunogenic/antigenic in macaques and humans. Separate groups of macaques were immunized with the peptide-cocktail by intravenous and subcutaneous routes using autologous dendritic cells (DC) and Freund's adjuvant, respectively. The vaccine elicited antigen specific IFN-γ-producing cells and T-cell proliferation, but not HIV-neutralizing antibodies. The vaccinated animals also exhibited efficient cross-clade cytolytic activity against target cells expressing envelope proteins corresponding to HIV-1 strains representative of multiple clades that increased after intravenous challenge with pathogenic SHIV KU2. Virus-neutralizing antibodies were either undetectable or present only transiently at low levels in the control as well as vaccinated monkeys after infection. Significant control of plasma viremia leading to undetectable levels was achieved in majority of vaccinated monkeys compared to mock-vaccinated controls. Monkeys vaccinated with the peptide-cocktail using autologous DC, compared to Freund's adjuvant, and the mock-vaccinated animals, showed significantly higher IFN-γ production, higher levels of vaccine-specific IFN-γ producing CD4 + cells and significant control of plasma viremia. These results support DC-based vaccine delivery and the utility of the conserved HIV-1 envelope peptide-cocktail, capable of priming strong cell-mediated immunity, for potential inclusion in HIV vaccination strategies.

Immunogenicity of a DNA prime and recombinant adenovirus boost regime significantly varies between rhesus macaques of Chinese and Indian origins

Due to an ever increasing shortage of rhesus macaques of Indian origin (InR) that have been generally used for preclinical AIDS vaccine trials in non-human primates, demand is rising for Chinese rhesus macaques (ChR). However, the immunogenicity of an AIDS vaccine candidate has not been compared in parallel in both rhesus macaque subspecies. ChR and InR were immunized with SIV/HIV DNA and adenovirus vaccine and their immune responses to SIV and HIV evaluated. SIV Gag- and Env-specific T-cell responses and SIV-specific lymphoproliferative responses measured in ChR were significantly weaker than those in InR (P < 0.05). By contrast, antibody responses to SIV Env, Tat, and Nef in ChR were stronger than those in InR (P < 0.05). Immunogenicity of an AIDS vaccine can vary significantly depending on the geographic origin implying genetic differences of macaques. This must be considered when describing and interpreting results of such vaccine studies.

Subdominant CD8+T-Cell Responses Are Involved in Durable Control of AIDS Virus Replication

"Elite controllers" are individuals that durably control human immunodeficiency virus or simian immunodeficiency virus replication without therapeutic intervention. The study of these rare individuals may facilitate the definition of a successful immune response to immunodeficiency viruses. Here we describe six Indian-origin rhesus macaques that have controlled replication of the pathogenic virus SIVmac239 for 1 to 5 years. To determine which lymphocyte populations were responsible for this control, we transiently depleted the animals' CD8+ cells in vivo. This treatment resulted in 100- to 10,000-fold increases in viremia. When the CD8+ cells returned, control was reestablished and the levels of small subsets of previously subdominant CD8+ T cells expanded up to 2,500-fold above pre-depletion levels. This wave of CD8+ T cells was accompanied by robust Gag-specific CD4 responses. In contrast, CD8+ NK cell frequencies changed no more than threefold. Together, our data suggest that CD8+ T cells targeting a small number of epitopes, along with broad CD4+ T-cell responses, can successfully control the replication of the AIDS virus. It is likely that subdominant CD8+ T-cell populations play a key role in maintaining this control.

Molecularly cloned SHIV-1157ipd3N4: a highly replication- competent, mucosally transmissible R5 simian-human immunodeficiency virus encoding HIV clade C Env.

Human immunodeficiency virus type 1 (HIV-1) clade C causes >50% of all HIV infections worldwide, and an estimated 90% of all transmissions occur mucosally with R5 strains. A pathogenic R5 simian-human immunodeficiency virus (SHIV) encoding HIV clade C env is highly desirable to evaluate candidate AIDS vaccines in nonhuman primates. To this end, we generated SHIV-1157i, a molecular clone from a Zambian infant isolate that carries HIV clade C env. SHIV-1157i was adapted by serial passage in five monkeys, three of which developed peripheral CD4(+) T-cell depletion. After the first inoculated monkey developed AIDS at week 137 postinoculation, transfer of its infected blood to a naïve animal induced memory T-cell depletion and thrombocytopenia within 3 months in the recipient. In parallel, genomic DNA from the blood donor was amplified to generate the late proviral clone SHIV-1157ipd3. To increase the replicative capacity of SHIV-1157ipd3, an extra NF-kappaB binding site was engineered into its 3' long terminal repeat, giving rise to SHIV-1157ipd3N4. This virus was exclusively R5 tropic and replicated more potently in rhesus peripheral blood mononuclear cells than SHIV-1157ipd3 in the presence of tumor necrosis factor alpha. Rhesus macaques of Indian and Chinese origin were next inoculated intrarectally with SHIV-1157ipd3N4; this virus replicated vigorously in both sets of monkeys. We conclude that SHIV-1157ipd3N4 is a highly replication-competent, mucosally transmissible R5 SHIV that represents a valuable tool to test candidate AIDS vaccines targeting HIV-1 clade C Env.

Ample Monkeys and Money Nurture Robust Research

SAN JUAN AND CAYO SANTIAGO, PUERTO RICO-- This country9s close ties to the United States, combined with its large colony of rhesus macaques of Indian origin, have spawned several collaborations with leading AIDS researchers from the mainland--a rarity in much of the Caribbean. (Read more.)

Initiation of antiretroviral therapy during chronic SIV infection leads to rapid reduction in viral loads and the level of T‐cell immune response

In the present era of increasing resistance of human immunodeficiency virus (HIV) to antiviral drugs, exploration of adjunct therapies directed at immune responses in combination with antiretroviral drugs may be of value for the treatment of acquired immunodeficiency syndrome. In this study, we designed a model for immune therapy using SIVmac251 infection in rhesus macaques. We explored the outcomes of primary infection on viral loads and the resulting T-cell immune responses in primates. The SIV-infected rhesus macaque model exhibited features similar to those observed in HIV-1 infection of humans. Major histocompatibility complex (MHC) segregation with viral loads were found to associate with viral containment and hence the duration of the disease-free latency period. Thus a better understanding of the relative roles of MHC class I allele in control of viral replication may provide important information for prophylactic or therapeutic vaccine designs. Mamu-A01 is significantly associated with higher immune response and control of viral replication. This allele is frequent in rhesus macaques of Indian origin (22%). Interestingly, Mamu-B01 (26% animals) was associated with lower immune responses and higher viral loads. Another allele, A08 was also predominantly present in 37% of the animals in this study. We observed higher viral replication in individual SIV-infected rhesus monkeys that did not demonstrate strong cellular immune responses. The results are important for understanding SIV disease progression in different MHC Mamu alleles and also for improving the interpretation and quality of pre-clinical studies in rhesus monkeys.