Simian immunodeficiency virus SIVagm dynamics in African green monkeys.
ABSTRACT The mechanisms underlying the lack of disease progression in natural simian immunodeficiency virus (SIV) hosts are still poorly understood. To test the hypothesis that SIV-infected African green monkeys (AGMs) avoid AIDS due to virus replication occurring in long-lived infected cells, we infected six animals with SIVagm and treated them with potent antiretroviral therapy [ART; 9-R-(2-phosphonomethoxypropyl) adenine (tenofovir) and beta-2,3-dideoxy-3-thia-5-fluorocytidine (emtricitabine)]. All AGMs showed a rapid decay of plasma viremia that became undetectable 36 h after ART initiation. A significant decrease of viral load was observed in peripheral blood mononuclear cells and intestine. Mathematical modeling of viremia decay post-ART indicates a half-life of productively infected cells ranging from 4 to 9.5 h, i.e., faster than previously reported for human immunodeficiency virus and SIV. ART induced a slight but significant increase in peripheral CD4(+) T-cell counts but no significant changes in CD4(+) T-cell levels in lymph nodes and intestine. Similarly, ART did not significantly change the levels of cell proliferation, activation, and apoptosis, already low in AGMs chronically infected with SIVagm. Collectively, these results indicate that, in SIVagm-infected AGMs, the bulk of virus replication is sustained by short-lived cells; therefore, differences in disease outcome between SIVmac infection of macaques and SIVagm infection of AGMs are unlikely due to intrinsic differences in the in vivo cytopathicities between the two viruses.
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ABSTRACT: The role of the accessory viral Nef protein as a multi-functional manipulator of the host cell that is required for effective replication of HIV and SIV in vivo is well established. It is unknown, however, whether Nef manipulates all or just specific subsets of CD4+ T cells that are the main targets of virus infection and differ substantially in their state of activation and importance for a functional immune system. Here, we analyzed the effect of Nef proteins differing in their TCR-CD3 downmodulation function in HIV infected human lymphoid aggregate cultures and peripheral blood mononuclear cells. We found that Nef efficiently downmodulates TCR-CD3 in naïve and memory CD4+ T cells and protects the latter against apoptosis. In contrast, highly proliferative CD45RA+CD45RO+CD4+ T cells were main producers of infectious virus but largely refractory to TCR-CD3 downmodulation. Such T cell subset-specific differences were also observed for Nef-mediated modulation of CD4 but not for enhancement of virion infectivity. Our results indicate that Nef predominantly modulates surface receptors on CD4+ T cell subsets that are not already fully permissive for viral replication. As a consequence, Nef-mediated downmodulation of TCR-CD3 that distinguishes most primate lentiviruses from HIV-1 and its vpu containing simian precursors may promote a selective preservation of central memory CD4+ T cells that are critical for the maintenance of a functional immune system. The Nef proteins of human and simian immunodeficiency viruses manipulate infected CD4+ T cells in multiple ways to promote viral replication and immune evasion in vivo. Here, we show that some effects of Nef are subset-specific. Downmodulation of CD4 and TCR-CD3 is highly effective in central memory CD4+ T cells and the latter Nef function protects this T cell subset against apoptosis. In contrast, highly activated/proliferating CD4+ T cells are largely refractory to receptor downmodulation but main producers of infectious HIV-1. Nef-mediated enhancement of virion infectivity, however, was observed in all T cell subsets examined. Our results provide new insights into how primate lentiviruses manipulate their target cells and suggest that the TCR-CD3 downmodulation function of Nef may promote a selective preservation of memory CD4+ T cells that are critical for immune function but has little effect on activated/proliferating CD4+T cells that are main targets for viral replication. Copyright © 2014, American Society for Microbiology. All Rights Reserved.Journal of Virology 12/2014; DOI:10.1128/JVI.03104-14 · 4.65 Impact Factor
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ABSTRACT: Damage to the intestinal mucosa results in the translocation of microbes from the intestinal lumen into the circulation. Microbial translocation has been proposed to trigger immune activation, inflammation, and coagulopathy, all of which are key factors that drive HIV disease progression and non-HIV comorbidities; however, direct proof of a causal link is still lacking. Here, we have demonstrated that treatment of acutely SIV-infected pigtailed macaques with the drug sevelamer, which binds microbial lipopolysaccharide in the gut, dramatically reduces immune activation and inflammation and slightly reduces viral replication. Furthermore, sevelamer administration reduced coagulation biomarkers, confirming the contribution of microbial translocation in the development of cardiovascular comorbidities in SIV-infected nonhuman primates. Together, our data suggest that early control of microbial translocation may improve the outcome of HIV infection and limit noninfectious comorbidities associated with AIDS.Journal of Clinical Investigation 05/2014; 124(6). DOI:10.1172/JCI75090 · 13.77 Impact Factor