Cross-species transmission of simian immunodeficiency virus from sooty mangabeys (SIVsm) into rhesus macaques, and subsequent emergence of pathogenic SIVmac, required adaptation to overcome restriction encoded by the macaque TRIM5 gene.

African green monkeys (genus Chlorocebus) can be infected with SIVagm, but do not develop AIDS. This natural host of SIV, like sooty mangabeys, maintains high levels of SIV replication but has evolved to avoid immunodeficiency. Elucidating the mechanisms that allow the natural hosts to co-exist with SIV without overt disease may provide crucial information to understand AIDS pathogenesis. Here we show: (1) many CD4+ T cells from African green monkeys down-regulate CD4 in vivo as they enter the memory pool, (2) down regulation of CD4 by memory T cells is independent of SIV infection, (3) the CD4− memory T cells maintain functions which are normally attributed to CD4 T cells including production of IL-2, production of IL-17, expression of FoxP3 and expression of CD40L (4) loss of CD4 expression protects these T cells from infection by SIVagm in vivo, and (5) these CD4− T cells can maintain MHC-II restriction. These data demonstrate that the absence of SIV-induced disease progression in natural hosts species may be partially explained by preservation of a subset of T cells that maintain CD4 T cell function while being resistant to SIV-infection in vivo.

The viral accessory protein Vpx is required for productive in vitro infection of macrophages by simian immunodeficiency virus from sooty mangabey monkeys (SIV(SM)). To evaluate the roles of Vpx and macrophage infection in vivo, we inoculated pigtailed macaques intravenously or intrarectally with the molecularly cloned, macrophage tropic, acutely pathogenic virus SIV(SM) PBj 6.6, or accessory gene deletion mutants (deltaVpr or deltaVpx) of this virus. Both wild-type and SIV(SM) PBj deltaVpx viruses were readily transmitted across the rectal mucosa. A subsequent 'stepwise' process of local amplification of infection and dissemination was observed for wild-type virus, but not for SIV(SM) PBj deltaVpx, which also showed considerable impairment of the overall kinetics and extent of its replication. In animals co-inoculated with equivalent amounts of wild-type and SIV(SM) Pbj deltaVpx intravenously or intrarectally, the deltaVpx mutant was at a strong competitive disadvantage. Vpx-dependent viral amplification at local sites of initial infection, perhaps through a macrophage-dependent mechanism, may be a prerequisite for efficient dissemination of infection and pathogenic consequences after exposure through either mucosal or intravenous routes.

In contrast to simian immunodeficiency viruses (SIVs), which induce immunodeficiency over a 1-to 3-year period, highly pathogenic simian-human immunodeficiency viruses (SHIVs) cause a complete, irreversible, and systemic depletion of CD4 ؉ T lymphocytes in rhesus monkeys within weeks of infection. By using small-molecule competitors specific for CCR5 and CXCR4 in ex vivo assays, we found that highly pathogenic SHIVDH12R exclusively uses CXCR4 for infection of rhesus peripheral blood mononuclear cells, whereas SIVmac239 and SIVsmE543 use CCR5 for entry into the same cells. During the period of peak virus production in SHIV DH12R-or SHIV89.6P-infected rhesus monkeys, massive elimination of CXCR4 ؉ naïve CD4 ؉ T cells occurred. In contrast, circulating CCR5 ؉ memory CD4 ؉ T cells were selectively depleted in rapidly progressing SIV-infected monkeys. At the time of their death, two SIV rapid progressors had experienced a nearly complete loss of the memory CD4 ؉ T cell subset from the blood and mesenteric lymph nodes. Thus, pathogenic SHIVs and SIVs target different subsets of CD4 ؉ T cells in vivo, with the pattern of CD4 ؉ T lymphocyte depletion being inextricably linked to chemokine receptor use. In the context of developing an effective prophylactic vaccine, which must potently control virus replication during the primary infection, regimens that suppress SHIVs might not protect monkeys against SIV or humans against HIV-1.

Prior studies demonstrated that immunization of macaques with simian immunodeficiency virus (SIV)Gag

The dynamics of plasma viremia were explored in a group of 12 simian immunodeficiency virus (SIV)infected rhesus macaques (Macaca mulatta) that had received prior immunization with either nonrecombinant or trivalent (gag-pol, env) SIV-recombinant vaccinia viruses. Three distinct patterns of viral replication observed during and following primary viremia accounted for significant differences in survival times. Highlevel primary plasma viremia with subsequently increasing viremia was associated with rapid progression to AIDS (n ‫؍‬ 2). A high-level primary plasma virus load with a transient decline and subsequent progressive increase in viremia in the post-acute phase of infection was associated with progression to AIDS within a year (n ‫؍‬ 6). Low levels of primary plasma viremia followed by sustained restriction of virus replication were associated with maintenance of normal lymphocyte subsets and intact lymphoid architecture (n ‫؍‬ 4), reminiscent of the profile observed in human immunodeficiency virus type 1-infected long-term nonprogressors. Three of four macaques that showed this pattern had been immunized with an SIV recombinant derived from the attenuated vaccinia virus, modified vaccinia virus Ankara. These data link the dynamics and extent of virus replication to disease course and suggest that sustained suppression of virus promotes long-term, asymptomatic survival of SIV-infected macaques. These findings also suggest that vaccine modulation of host immunity may have profound beneficial effects on the subsequent disease course, even if sterilizing immunity is not achieved.

The distribution and levels of simian immunodeficiency virus (SIV) in tissues and plasma were assessed in naturally infected African green monkeys (AGM) of the vervet subspecies (Chlorocebus pygerythrus) by limitingdilution coculture, quantitative PCR for viral DNA and RNA, and in situ hybridization for SIV expression in tissues. A wide range of SIV RNA levels in plasma was observed among these animals (<1,000 to 800,000 copies per ml), and the levels appeared to be stable over long periods of time. The relative numbers of SIV-expressing cells in tissues of two monkeys correlated with the extent of plasma viremia. SIV expression was observed in lymphoid tissues and was not associated with immunopathology. Virus-expressing cells were observed in the lamina propria and lymphoid tissue of the gastrointestinal tract, as well as within alveolar macrophages in the lung tissue of one AGM. The range of plasma viremia in naturally infected AGM was greater than that reported in naturally infected sooty mangabeys. However, the degree of viremia in some AGM was similar to that observed during progression to AIDS in human immunodeficiency virus-infected individuals. Therefore, containment of viremia is an unlikely explanation for the lack of pathogenicity of SIVagm in its natural host species, AGM. Human immunodeficiency virus type 1 (HIV-1) is a member of a large family of nonhuman primate lentiviruses which have been designated simian immunodeficiency viruses (SIVs). At the present time, SIVs from at least seven African monkey species have been identified and molecularly characterized. The genetic relationships among five of these SIV strains isolated from sooty mangabey monkeys (Cercocebus atys; SIVsm), mandrills (Mandrillus sphinx; SIVmnd), Sykes monkeys (Cercopithecus albogularis mitis; SIVsyk), African green monkeys, (AGM; Chlorocebus spp.; SIVagm), and chimpanzees (Pan troglodytes; SIVcpz) have been reviewed previously (23,25,44). Briefly, SIV isolates segregate phylogenetically, based upon their species of origin, into at least five lineages represented by SIVsm, SIVagm, SIVsyk, SIVlhoest (9,26), and SIVcpz with a number of additional novel strains from other primates recently characterized (12,18). The SIVagm lineage consists of four distinct subtypes that cluster depending upon the species of AGM from which they were isolated, i.e

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