Comparison of Simian Immunodeficiency Virus SIVagmVer Replication and CD4
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            T-Cell Dynamics in Vervet and Sabaeus African Green Monkeys

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Simian immunodeficiency virus (SIV) infection in African nonhuman primate (NHP) natural hosts is usuallynonpathogenic, despite high levels of virus replication. We have previously shown that chronic SIV infection in sooty mangabeys (SMs) and African green monkeys (AGMs) is associated with low levels of immune activation and bystander T cell apoptosis. To compare these features with those observed in another natural host, the mandrill (MND), we conducted a cross-sectional survey of the 23 SIV-infected and 25 uninfected MNDs from the only semifree colony of mandrills available worldwide. Viral loads (VLs) were determined and phenotypic and functional analysis of peripheral blood-and lymph node-derived lymphocytes was performed. We found that mandrills chronically infected with SIVmnd-1 or SIVmnd-2 have similar levels of viral replication, and we observed a trend toward lower CD4 ؉ T cell counts in chronically SIVmnd-2-infected MNDs than SIVmnd-1-infected MNDs. No correlation between CD4؉ T cell counts and VLs in SIV-infected MNDs could be established. Of note, the levels of T cell activation, proliferation, and apoptosis were comparable between SIVmnd-1-and SIVmnd-2-infected MNDs and to those observed in uninfected animals, with the only exception being an increase in tumor necrosis factor alpha-producing CD8 ؉ T cells in SIVmnd-2-infected MNDs. Overall, these findings recapitulate previous observations in SIV-infected SMs and AGMs and lend further evidence to the hypothesis that low levels of immune activation protect natural SIV hosts from disease progression.

mentioning

confidence: 99%

Immunovirological Analyses of Chronically Simian Immunodeficiency Virus SIVmnd-1- and SIVmnd-2-Infected Mandrills (Mandrillus sphinx)

Apetrei

Sumpter

Souquière

et al. 2011

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“…With regard to the hypothesis that virus replication mainly occurs in macrophages, there is some evidence against this: (i) the dynamics of virus replication during acute infection is strikingly similar between progressive and nonprogressive SIV infections (51), which likely would not be the case if replication were supported by long-lived infected cells that produce virus slowly; (ii) the massive acute depletion of mucosal CD4 ϩ T cells suggests that these cells are the SIV targets (19,48); moreover, although this massive mucosal CD4 ϩ T-cell depletion involves all the CD4 ϩ T-cell subsets, the effector memory CD4 ϩ T-cell pool is the most susceptible and shows only minor restoration during chronic infection (19,48), similar to pathogenic HIV-1 and SIV infections (38,56); (iii) we and others (15) have provided direct evidence by in situ hybridization that, during acute infection of AGMs, SIVagm replicates in lymphocytes and not in macrophages (Fig. 2) (47).…”

Section: Discussionmentioning

confidence: 99%

“…In order to model the dynamics of virus replication, thorough sampling schedules during the primary SIVagm.sab infection and antiretroviral treatment were designed. Blood (4.9 ml, EDTA anticoagulated) was collected from the femoral vein at days Ϫ7 and 0, 3,6,8,10,13,15,18,20,28,30,42,56,72, 100, 132, 185 post-SIVagm.sab inoculation. Moreover, every 7 days between day 100 and day 132, 4.9 ml of blood was collected (with EDTA) to determine the weekly variation of VLs in SIVagm.sab-infected AGMs.…”

Section: Animalsmentioning

confidence: 99%

Simian Immunodeficiency Virus SIVagm Dynamics in African Green Monkeys

Pandrea

Ribeiro

Gautam³

et al. 2008

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100

112

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.

“…A real-time RT-PCR assay for quantitation of viral RNA in plasma was performed as previously described (19).…”

Section: Methodsmentioning

confidence: 99%

Homeostatic Cytokines Induce CD4 Downregulation in African Green Monkeys Independently of Antigen Exposure To Generate Simian Immunodeficiency Virus-Resistant CD8αα T Cells

Perkins

Briant

Calantone

et al. 2014

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African green monkeys (AGMs; genus Chlorocebus) are a natural host of simian immunodeficiency virus (SIV AGM ). As they do not develop simian AIDS, there is great interest in understanding how this species has evolved to avoid immunodeficiency. Adult African green monkeys naturally have low numbers of CD4 T cells and a large population of major histocompatibility complex class II-restricted CD8␣ dim T cells that are generated through CD4 downregulation in CD4 ؉ T cells. Mechanisms that drive this process of CD4 downregulation are unknown. Here, we show that juvenile AGMs accelerate CD4-to-CD8␣␣ conversion upon SIV infection and avoid progression to AIDS. The CD4 downregulation induced by SIV infection is not limited to SIV-specific T cells, and vaccination of an adult AGM who had a negligible number of CD4 T cells demonstrated that CD4 downregulation can occur without antigenic exposure. Finally, we show that the T cell homeostatic cytokines interleukin-2 (IL-2), IL-7, and IL-15 can induce CD4 downregulation in vitro. These data identify a mechanism that allows AGMs to generate a large, diverse population of T cells that perform CD4 T cell functions but are resistant to SIV infection. A better understanding of this mechanism may allow the development of treatments to induce protective CD4 downregulation in humans. IMPORTANCE Many African primate species are naturally infected with SIV. African green monkeys, one natural host species, avoid simian AIDS by creating a population of T cells that lack CD4, the human immunodeficiency virus/SIV receptor; therefore, they are resistant to infection. However, these T cells maintain properties of CD4؉ T cells even after receptor downregulation and preserve immune function. Here, we show that juvenile AGMs, who have not undergone extensive CD4 downregulation, accelerate this process upon SIV infection. Furthermore, we show that in vivo, CD4 downregulation does not occur exclusively in antigen-experienced T cells. Finally, we show that the cytokines IL-2, IL-7, and IL-15, which induce homeostatic T cell proliferation, lead to CD4 downregulation in vitro; therefore, they can provide signals that lead to antigen-independent CD4 downregulation. These results suggest that if a similar process of CD4 downregulation could be induced in humans, it could provide a cure for AIDS.