Sooty Mangabey Monkeys Research Articles

A Review of Evidence Related to the Zoonotic Characteristics of the Monkeypox Virus.

The 2022 monkeypox virus (MPXV) outbreaks spurred global public health concern. In response, we undertook a living systematic review of its zoonotic characteristics, including potential reservoirs and susceptible species, transmissibility, and clinical presentation in nonhuman species. Electronic database searches yielded 148 eligible records published between 2000 and 2022. Primary reservoirs remain unidentified, with natural isolation identified in 2 species, the sooty mangabey monkey and rope squirrel. Transmission primarily occurs from animals to humans, but evidence of reverse zoonosis has emerged. Data on clinical infection and manifestations are sparse, with evidence of potentially susceptible species drawn primarily from experimental studies. Only 10% of articles were appropriate for quality assessment and most of these were rated as critically low. Overall, while evidence regarding MPXV exists, the quality of data are extremely poor, resulting in significant uncertainty regarding MPXV's zoonotic traits. High-quality empirical research to understand the impact of MPXV on animal and human populations is warranted.

A REVIEW ON MONKEY POX DISEASE

After the disastrous COVID-19 pandemic, now, monkey pox has spreaded its legs all over the world. Disease originated in Africa but its outbreak occurred in 89 countries since January 2022. As per the World Health Organization report, in between January 1, 2022, and August 10, 2022, 27,814 confirmed cases and 11 deaths occurred across 89 countries. Monkey pox is a viral infection which may occur in humans as well as in animals. Rope squirrel (Funisciurus spp.), Gambian pouched rat (Cricetomys gambianus), and Sooty mangabey monkey (Cercocebus atys) are suspected reservoir host for monkey pox. Its symptoms are similar to but milder than small pox. As orthopox viruses are morphologically identical to each other, Polymerase chain reaction is only test for detection of monkey pox-specific DNA signatures. There is no specific treatment for monkey pox infection but as monkey pox and small pox infections are hereditarily comparative so antiviral medications and antibodies created to safeguard against small pox are generally prescribed to prevent and treat monkey pox. One of the important measures for prevention from monkey pox is small pox vaccination to the individual and also to the healthy people in occupation who are at high risk of exposure except in immunocompromised individuals.

Urogenital Lesions in Nonhuman Primates at 2 National Primate Research Centers.

Given their genetic and anatomic similarities to humans, nonhuman primates (NHPs) may serve as animal models for urogenital diseases of humans. The purpose of this study was to examine the frequency of spontaneous urogenital lesions occurring over a 30-year period at the Yerkes and Southwest National Primate Research Centers and to compare and contrast lesions occurring in Old World versus New World primates. Lesions occurring in the chimpanzee (Pan troglodytes), baboon (Papio spp.), rhesus macaque (Macaca mulatta), cynomolgus macaque (Macaca fascicularis), pig-tailed macaque (Macaca nemestrina), sooty mangabey (Cercocebus atys), common marmoset (Callithrix jacchus), cotton-top tamarin (Sanguinus oedipus), and squirrel monkey (Saimiri sciureus) are discussed. The most common lesions of the kidney were medullary amyloidosis, renal cysts, renal tubular degeneration, glomerulonephritis or glomerulopathy, nephritis, nephrocalcinosis, pyelonephritis, and hydronephrosis. Specific causes of renal tubular disease included pigmentary nephrosis and tubular lipidosis. Renal tumors, including renal adenoma and carcinoma, lymphoma, and nephroblastoma, were infrequent diagnoses in all species. Endometriosis was the most frequently diagnosed lesion of the female genital tract. Of the animals examined in this study, it was most frequent in Old World primates. Leiomyoma was the most common uterine tumor. Granulosa cell tumor was the most frequently observed neoplasm of the ovaries, followed by teratoma. Of animals included in the study, most ovarian tumors occurred in baboons. Neoplasms of the male reproductive tract included interstitial cell tumor, seminoma, penile squamous cell carcinoma, penile papilloma, and histiocytoma. In New World monkeys, renal lesions were reported more frequently than genital lesions.

Human immunodeficiency virus type 2 (HIV-2) dynamics and whole genome deep sequence analysis in Mauritian-origin cynomolgus macaques (Macaca fascicularis)

Human immunodeficiency virus type 2 (HIV-2) is a pathogenic human retrovirus with a distinct natural history and lineage derivation from pandemic HIV-1. HIV-2 infections in humans are the result of zoonotic transmission from sooty mangabey monkeys naturally infected with SIVsm. Unlike HIV-1, HIV-2 infects other non-human primate species, including baboons and macaques. We determined the infectivity and infection kinetics of a Gambian-origin HIV-2 isolate HIV-2SBL6669 strain in Mauritian-derived cynomolgus macaques (MCM) in the context of a heterologous superinfection resistance study. The ability of HIV-2 to replicate in unvaccinated MCM with limited host genetic MHC and TRIM5 spectrum was determined where the kinetics of plasma HIV-2 RNA mimic the phenotypic response typically observed in HIV-2-infected humans. HIV-2SBL669 replication is not completely restricted in this species and may establish a persistent infection. This is determined by moderate peak viral loads (105–6 log10 HIV-2 RNA copies/ml) controlling to a low level determined by qRT-PCR and detectable in-situ hybridisation signals in lymphoid tissue 20 weeks after challenge. In MCM vaccinated for 20 weeks with an attenuated SIV, we observed high levels of superinfection resistance as determined by virus-specific PCR analysis of tissues and low total plasma viral RNA levels in vaccinates compared to unvaccinated HIV-2 controls. Recovery of whole viral genome and next generation sequence analysis of challenge controls, including low-level breakthrough variants characterises viral challenge and vaccine-escape viruses. HIV-2 in cynomolgus macaques recapitulates many of the features of HIV-2 infections in humans.

Diversity of Primate Lentiviruses Rebooted

Highlight: The present report reveals for the first time natural lentiviral infection of wild Indian NHPs, rhesus monkeys (Macaca mulatta) and langurs (Semnopithecus entellus) by SIVs that are phylogenetically diverse from all known SIVs, including “SIVmac”, which infects captive rhesus monkeys. The novel SIVs are intriguingly homologous to HIV-1, based on serology and partial lentiviral genomic sequence analyses. Diverse lenti-viruses infect human and nonhuman primates (NHPs). There are more than 45 different “species-specific” simian immunodeficiency viruses (SIVs) that infect their cognate NHP hosts in natural habitats in Africa. Indian NHPs are not known to be infected by SIVs in the wild. Conventionally SIVs are named after their natural hosts, except for SIVmac, which infects captive rather than wild rhesus macaques. SIVmac is therefore a misnomer. It is a genetic variant of the African SIVsmm, which infects wild African sooty mangabey monkeys. SIVsmm is the progenitor of human immunodeficiency virus (HIV-2), while SIVcpz that infects wild chimpanzees is the progenitor of HIV-1. Although natural infections cannot be easily studied in wild NHP populations, we have previously reported co-infection of wild Indian NHPs by other retroviruses: simian retroviruses (SRVs) and Simian Foamy viruses (SFV). Apart from zoonosis, transmission of pathogens from humans to animals: anthroponosis, has also been reported in literature.

TRIM5α Resistance Escape Mutations in the Capsid Are Transferable between Simian Immunodeficiency Virus Strains

Many strains of SIV from sooty mangabey monkeys are susceptible to resistance by common rhesus macaque TRIM5α alleles and result in reduced virus acquisition and replication in macaques that express these restrictive alleles. We previously observed that spontaneous variations in the capsid gene were associated with improved replication in macaques, and the introduction of two amino acid changes in the capsid transfers this improved replication to the parent clone. In the present study, we introduced these mutations into a related but distinct strain of SIV that is commonly used for challenge studies for vaccine trials. These mutations also improved the replication of this strain in macaques with the restrictive TRIM5α genotype and thus will eliminate the confounding effects of TRIM5α in vaccine studies.

Vif Proteins from Diverse Human Immunodeficiency Virus/Simian Immunodeficiency Virus Lineages Have Distinct Binding Sites in A3C.

The APOBEC3 restriction factors can serve as potential barriers to lentiviral cross-species transmissions. Vif proteins from lentiviruses counteract APOBEC3 by proteasomal degradation. In this study, we found that monkey-derived A3C, rhA3C and smmA3C, were resistant to HIV-1 Vif. This was determined by A3C residues N/H130 and Q133. However, HIV-2, SIVagm, and SIVmac Vif proteins were found to be able to mediate the depletion of all tested primate A3C proteins. In addition, we identified a natural HIV-1 Vif (F-1 Vif) that was inactive in the degradation of hA3C/hA3F. Here, we provide for the first time a model that explains how an internal salt bridge of E171-K167-D101 influences Vif-mediated degradation of hA3C/hA3F. This finding provides a novel way to develop HIV-1 inhibitors by targeting the internal interactions of the Vif protein.

Development of HTLV-1 associated myelopathy/tropical spastic paraparesis in a patient with simian T-lymphotropic virus type 1-like infection.

Virus transmission from various wild and domestic animals contributes to increased risk of emerging infectious diseases in human populations. HTLV-1 is a human retrovirus associated with acute T-cell leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), which originated from zoonotic transmission from various African and Asian nonhuman primates (NHPs). Similar to HTLV-1, the simian counterpart, STLV-1, causes chronic infection and leukemia and lymphoma in naturally infected monkeys. However, other clinical syndromes typically seen in human such as a chronic progressive myelopathy have not been observed in NHPs. Little is also known about the development of any neurologic and inflammatory diseases in human populations infected with STLV-1-like viruses following NHP exposure. We identified and analyzed the complete genome of a primate T lymphotropic virus type 1 (PTLV-1) isolated from a patient with typical HAM/TSP who resides in the United States but was born in Liberia. Using a novel droplet digital PCR for the detection of the HTLV-1 tax gene, the proviral load in PBMC was 14.01%; however there was a distinct difference in fluorescence amplitude compared to all other H!M/TSP patient's, suggesting viral heterogeneity. A complete PTLV-1 proviral genome was amplified from DNA extracted from the PBMCs of the HAM/TSP patient using PCR to generate nine overlapping subgenomic fragments. Phylogenetic analysis of PTLV-1 env and LTR regions showed the virus was highly related with PTLV-1 from sooty mangabey monkeys and humans exposed from NHPs in West Africa. These results suggest the patient is likely infected with STLV-1, suggesting for the first time that viral transmission from monkey to human may be associated with a chronic progressive neurologic disease.

Lv4 Is a Capsid-Specific Antiviral Activity in Human Blood Cells That Restricts Viruses of the SIVMAC/SIVSM/HIV-2 Lineage Prior to Integration.

HIV-2 and SIVMAC are AIDS-causing, zoonotic lentiviruses that jumped to humans and rhesus macaques, respectively, from SIVSM-bearing sooty mangabey monkeys. Cross-species transmission events such as these sometimes necessitate virus adaptation to species-specific, host restriction factors such as TRIM5. Here, a new human restriction activity is described that blocks viruses of the SIVSM/SIVMAC/HIV-2 lineage. Human T, B, and myeloid cell lines, peripheral blood mononuclear cells and dendritic cells were 4 to >100-fold less transducible by VSV G-pseudotyped SIVMAC, HIV-2, or SIVSM than by HIV-1. In contrast, transduction of six epithelial cell lines was equivalent to that by HIV-1. Substitution of HIV-1 CA with the SIVMAC or HIV-2 CA was sufficient to reduce HIV-1 transduction to the level of the respective vectors. Among such CA chimeras there was a general trend such that CAs from epidemic HIV-2 Group A and B isolates were the most infectious on human T cells, CA from a 1° sooty mangabey isolate was the least infectious, and non-epidemic HIV-2 Group D, E, F, and G CAs were in the middle. The CA-specific decrease in infectivity was observed with either HIV-1, HIV-2, ecotropic MLV, or ALV Env pseudotypes, indicating that it was independent of the virus entry pathway. As2O3, a drug that suppresses TRIM5-mediated restriction, increased human blood cell transduction by SIVMAC but not by HIV-1. Nonetheless, elimination of TRIM5 restriction activity did not rescue SIVMAC transduction. Also, in contrast to TRIM5-mediated restriction, the SIVMAC CA-specific block occurred after completion of reverse transcription and the formation of 2-LTR circles, but before establishment of the provirus. Transduction efficiency in heterokaryons generated by fusing epithelial cells with T cells resembled that in the T cells, indicative of a dominant-acting SIVMAC restriction activity in the latter. These results suggest that the nucleus of human blood cells possesses a restriction factor specific for the CA of HIV-2/SIVMAC/SIVSM and that cross-species transmission of SIVSM to human T cells necessitated adaptation of HIV-2 to this putative restriction factor.

Vif Proteins from Diverse Primate Lentiviral Lineages Use the Same Binding Site in APOBEC3G

APOBEC3G (A3G) is a cytidine deaminase that restricts human immunodeficiency virus type 1 (HIV-1) and other lentiviruses. Most of these viruses encode a Vif protein that directly binds A3G and leads to its proteasomal degradation. Both Vif proteins of HIV-1 and African green monkey simian immunodeficiency virus (SIVagm) bind residue 128 of A3G. However, this position does not control the A3G degradation by Vif variants derived from HIV-2 and SIVmac, which both originated from SIV of sooty mangabey monkeys (SIVsmm), suggesting that the A3G binding site for Vif proteins of the SIVsmm/HIV-2 lineage differs from that of HIV-1. To map the SIVsmm Vif binding site of A3G, we performed immunoprecipitations of individual A3G domains, Vif/A3G degradation assays and a detailed mutational analysis of human A3G. We show that A3G residue 129, but not the adjacent position 128, confers susceptibility to degradation by SIVsmm Vif. An artificial A3G mutant, the P129D mutant, was resistant to degradation by diverse Vifs from HIV-1, HIV-2, SIVagm, and chimpanzee SIV (SIVcpz), suggesting a conserved lentiviral Vif binding site. Gorilla A3G naturally contains a glutamine (Q) at position 129, which makes its A3G resistant to Vifs from diverse lineages. We speculate that gorilla A3G serves as a barrier against SIVcpz strains. In summary, we show that Vif proteins from distinct lineages bind to the same A3G loop, which includes positions 128 and 129. The multiple adaptations within this loop among diverse primates underscore the importance of counteracting A3G in lentiviral evolution.

A lamprey monoclonal VLR antibody recognizes a novel plasma cell antigen (P3020)

Abstract Variable lymphocyte receptor B (VLRB) antibodies of the jawless sea lamprey are composed of leucine-rich repeat (LRR) units instead of the Ig-based units of conventional mammalian antibodies. Structural analyses of three monoclonal VLRB antibodies paired with their cognate antigens indicate that antigens bind to variable residues in the beta-sheets located on the inner concave surface of the solenoid VLRB protein and to a flexible loop structure protruding from the C-terminal LRR. We recently demonstrated that VLRB antibodies can be used in standard laboratory techniques such as flow immunocytometry, western blotting, immunoprecipitation and mass spectrometry-based protein identification. In an effort to identify novel biomarkers on human plasma cells, we screened a VLRB library generated from lamprey larvae immunized with human bone marrow of multiple myeloma patient and isolated a monoclonal VLRB antibody (MM3) that selectively recognized plasma cells from myeloma patients, normal individuals and two non-human primates, Rhesus macaque and Sooty mangabey monkeys. Surprisingly, screening of a diverse panel of human cell lines indicated expression of the MM3 antigen by two of nine B cell lines, but not by plasmacytoma cell lines. Trypsin and periodate sensitivity of the MM3 epitope suggested the glycoprotein nature of the cell membrane antigen. We conclude that the recombinant VLR MM3 antibody recognizes a novel plasma cell marker.

Acute SIV Infection in Sooty Mangabey Monkeys Is Characterized by Rapid Virus Clearance from Lymph Nodes and Absence of Productive Infection in Germinal Centers

Lymphoid tissue immunopathology is a characteristic feature of chronic HIV/SIV infection in AIDS-susceptible species, but is absent in SIV-infected natural hosts. To investigate factors contributing to this difference, we compared germinal center development and SIV RNA distribution in peripheral lymph nodes during primary SIV infection of the natural host sooty mangabey and the non-natural host pig-tailed macaque. Although SIV-infected cells were detected in the lymph node of both species at two weeks post infection, they were confined to the lymph node paracortex in immune-competent mangabeys but were seen in both the paracortex and the germinal center of SIV-infected macaques. By six weeks post infection, SIV-infected cells were no longer detected in the lymph node of sooty mangabeys. The difference in localization and rate of disappearance of SIV-infected cells between the two species was associated with trapping of cell-free virus on follicular dendritic cells and higher numbers of germinal center CD4+ T lymphocytes in macaques post SIV infection. Our data suggests that fundamental differences in the germinal center microenvironment prevent productive SIV infection within the lymph node germinal centers of natural hosts contributing to sustained immune competency.

Die Evolution von HIV, dem humanen Immunschwächevirus

HIV-1 evolved by zoonotic transmission of chimpanzee lentivirus to man around 1920. HIV-1 is now divided in four groups that had been transmitted by at least four independent events. HIV-2 originates from sooty mangabey monkeys in West Africa and was transmitted to man around 1940. For HIV-2 at least eight transmission events, forming the groups A to H, led to the ongoing epidemic. Regarding HIV and the AIDS epidemic it should be prevented that further animal viruses will be introduced to the human population.

Nonpathogenic Simian Immunodeficiency Virus Infections

The simian immunodeficiency viruses (SIVs) are a diverse group of viruses that naturally infect a wide range of African primates, including African green monkeys (AGMs) and sooty mangabey monkeys (SMs). Although natural infection is widespread in feral populations of AGMs and SMs, this infection generally does not result in immunodeficiency. However, experimental inoculation of Asian macaques results in an immunodeficiency syndrome remarkably similar to human AIDS. Thus, natural nonprogressive SIV infections appear to represent an evolutionary adaptation between these animals and their primate lentiviruses. Curiously, these animals maintain robust virus replication but have evolved strategies to avoid disease progression. Adaptations observed in these primates include phenotypic changes to CD4(+) T cells, limited chronic immune activation, and altered mucosal immunity. It is probable that these animals have achieved a unique balance between T-cell renewal and proliferation and loss through activation-induced apoptosis, and virus-induced cell death. A clearer understanding of the mechanisms underlying the lack of disease progression in natural hosts for SIV infection should therefore yield insights into the pathogenesis of AIDS and may inform vaccine design.

Inhibition of cellular activation of retroviral replication by CD8+ T cells derived from non-human primates.

To test the hypothesis that CD8+ T cells inhibit viral replication at the level of cellular activation, an Epstein-Barr virus (EBV)-transformed cell line (FEc1) from a simian immunodeficiency virus (SIV)-seropositive sooty mangabey monkey was transfected with a human CD4 gene and shown to be replication-competent for HIV-1, HIV-2 and SIV. Utilizing a dual-chamber culture system, it was found that inhibition of viral replication can be mediated by a soluble factor. The FEc1 cell line was transiently transfected with an LTR-driven CAT reporter gene. It was found that autologous CD8+ T cells markedly inhibited CAT activity. Furthermore, co-transfection of the FEc1 cell line with an LTR-driven tat plasmid and LTR-CAT was able to quantitatively mitigate the suppressive effect. Thus, this inhibition appears to be directed at cellular mechanisms of viral transcription. Control transfections with an LTR-driven CAT plasmid with a mutation at the NFkB binding site yielded no CAT activity, suggesting that most viral replication as measured by CAT activity is dependent, to a large extent, upon cellularly derived NFkB binding proteins.

Phylogénie des SIV et des VIH

Emergence of human immunodeficiency viruses HIV-1 and HIV-2 results from interspecies transmission from simian viruses SIV. SIVcpzPtt infecting chimpanzees, and from which the HIV-1 (subgroups M and N) is derived is still found in the Pan troglodytes troglodytes population of south Cameroon chimpanzees. The ancestor of HIV-1 group O, is found in the Gorilla residing in Western Africa, but chimpanzees are in fact the initial reservoir of the SIV viruses SIVgor, and it is still unclear whether the group O HIV-1 has been transmitted to humans by gorillas and/or chimpanzees. At least eight interspecies transmissions between and humans implicating SIVsmm (from sooty mangabey monkeys) have occurred, corresponding to the eight VIH-2 groups. Since habits of hunting and meat preparation in the bush still persistently expose humans in Africa to SIV infection, new interspecies transmission of these viruses remains a possibility.

The role of the armadillo and sooty mangabey monkey in human leprosy

The armadillo was the first animal model of leprosy. Its role in the transmission of leprosy remains controversial. The sooty mangabey model of leprosy led to the discovery that rhesus monkeys were more susceptible to leprosy when coinfected with simian immunodeficiency virus (SIV), but that leprosy may play a protective role against acquired immunodeficiency syndrome (AIDS) mortality. Recently, molecular methods have been developed for leprosy and may help resolve the role of zoonoses in leprosy. The recent identification of a case of leprosy in a native-born American on the east coast of the USA and the identification of leprosy as an immunologic reconstitution inflammatory syndrome (IRIS) in human immunodeficiency virus (HIV)-positive cases raise the question of what role zoonoses may play in leprosy. Leprosy in armadillos and sooty mangabeys has been manipulated by human experimentation. In the case of the armadillo, further study, including molecular techniques, is required to elucidate the role of the armadillo as a zoonosis in human leprosy. Experimentation with the sooty mangabey led to the discovery of an interaction between SIV and leprosy in rhesus monkeys, and prompted the continued investigation of the relationship between HIV and leprosy.

Tissue-specific reduction in DC-SIGN expression correlates with progression of pathogenic simian immunodeficiency virus infection

Studies were undertaken to determine whether previously described reductions in splenic DC-SIGN expression in simian acquired immune deficiency syndrome (AIDS) are limited to pathogenic simian immunodeficiency virus (SIV) infection. DC-SIGN expression was evaluated by immunohistochemistry in lymphoid tissues from AIDS-susceptible Asian macaque monkeys as compared with AIDS-resistant sooty mangabey monkeys in the presence and absence of SIV infection. The phenotype of DC-SIGN+ cells in susceptible and resistant species was identical and most consistent with macrophage identity. Significantly lower levels of DC-SIGN expression were identified in spleen, mesenteric lymph node, and bone marrow of macaques with AIDS (P<0.05). Reduced levels of splenic DC-SIGN correlated significantly with CD4T cell depletion in long-term pathogenic infection of macaques (P<0.01), whereas SIV-infected mangabeys retained high levels of DC-SIGN expression in spleen despite persistent infection. Reduced expression of DC-SIGN in spleen specifically characterizes pathogenic forms of SIV infection, correlates with disease progression, and may contribute to SIV pathogenesis.

Depletion of CD8+ Cells in Sooty Mangabey Monkeys Naturally Infected with Simian Immunodeficiency Virus Reveals Limited Role for Immune Control of Virus Replication in a Natural Host Species

SIV infection of sooty mangabeys (SMs), a natural host species, does not cause AIDS despite high-level virus replication. In contrast, SIV infection of nonnatural hosts such as rhesus macaques (RMs) induces an AIDS-like disease. The depletion of CD8+ T cells during SIV infection of RMs results in marked increases in plasma viremia, suggesting a key role for CD8+ T cells in controlling levels of SIV replication. To assess the role that CD8+ T cells play in determining the virologic and immunologic features of nonpathogenic SIV infection in SMs, we transiently depleted CD8+ T cells in SIV-infected and uninfected SMs using a CD8alpha-specific Ab (OKT8F) previously used in studies of SIV-infected RMs. Treatment of SMs with the OKT8F Ab resulted in the prompt and profound depletion of CD8+ T cells. However, in contrast to CD8+ cell depleted, SIV-infected RMs, only minor changes in the levels of plasma viremia were observed in most SIV-infected SMs during the period of CD8+ cell deficiency. Those SMs demonstrating greater increases in SIV replication following CD8+ cell depletion also displayed higher levels of CD4+ T cell activation and/or evidence of CMV reactivation, suggesting that an expanded target cell pool rather than the absence of CD8+ T cell control may have been primarily responsible for transient increases in viremia. These data indicate that CD8+ T cells exert a limited influence in determining the levels of SIV replication in SMs and provide additional evidence demonstrating that the absence of AIDS in SIV-infected SMs is not due to the effective control of viral replication by cellular immune responses.

Naturally SIV‐infected sooty mangabeys: are we closer to understanding why they do not develop AIDS?

Simian immunodeficiency viruses (SIV) infection of sooty mangabey (SM) monkeys (Cercocebus atys), a natural host species, does not induce CD4+ T cell depletion and acquired immunodeficiency syndrome (AIDS) despite chronic high levels of virus replication. In contrast, SIV infection of non-natural host species, such as rhesus macaques (RM), induces a disease that closely resembles AIDS in humans. The mechanisms underlying the lack of disease progression in SIV-infected SMs are incompletely understood, but certainly reflect a complex evolutionary adaptation whereby the host immune system is not significantly damaged by the highly replicating virus. It is now widely recognized that a better understanding of these mechanisms may provide clues to the pathogenesis of immunodeficiency in HIV-infected humans. In this article I discuss five different hypotheses that may account for the non-pathogenic course of infection in SIV-infected SMs and briefly review the available data supporting each of these hypotheses.