The AIDS resistance of naturally SIV-infected sooty mangabeys is independent of cellular immunity to the virus

Abstract

In contrast to human immunodeficiency virus (HIV)-infected humans, natural hosts for simian immunodeficiency virus (SIV) very rarely progress to acquired immunodeficiency syndrome (AIDS).While the mechanisms underlying this disease resistance are still poorly understood, a consistent feature of natural SIV infection is the absence of the generalized immune activation associated with HIV infection. To investigate the immunologic mechanisms underlying the absence of AIDS in SIV-infected sooty mangabeys (SMs), a natural host species, we performed a detailed analysis of the SIV-specific cellular immune responses in 110 SIV-infected SMs. We found that while SIV-specific T-cell responses are detectable in the majority of animals, their magnitude and breadth are, in fact, lower than what has been described in HIVinfected humans, both in terms of cytokine production (ie, IFN-␥, TNF-␣, and IL-2) and degranulation (ie, CD107a expression). Of importance, SIV-specific Tcell responses were similarly low when either SIVmac239-derived peptides or autologous SIVsmm peptides were used as stimuli. No correlation was found between SIV-specific T-cell responses and either viral load or CD4 ؉ T-cell count, or between these responses and markers of T-cell activation and proliferation. These findings indicate that the absence of AIDS in naturally SIV-infected sooty mangabeys is independent of a strong cellular immune response to the virus. IntroductionThe acquired immunodeficiency syndrome (AIDS) pandemic originated from zoonotic transmission of simian immunodeficiency viruses (SIVs) from infected African monkey species to humans. 1 Of the natural SIV hosts, sooty mangabeys (Cercocebus atys, SMs) are of interest for 2 main reasons. First, SIVsmm, the virus infecting SMs, is the origin of the human immunodeficiency virus 2 (HIV-2) epidemic in humans. 1-3 Second, SIVsmm is the source of the prototype SIVmac strains (ie, SIVmac239, SIVmac251) that induce an AIDS-like disease in the rhesus macaque (RM), a nonnatural host for SIV, and consequently are widely used for studies of AIDS pathogenesis and vaccines. 2,4-6 SIVsmm and HIV-1/2 share many features in terms of life cycle and molecular structure, and the extent of virus replication is similarly high in naturally SIV-infected SMs and HIV-infected humans. 7-9 However, the outcome of these infections is strikingly different. The vast majority of HIV-infected humans, unless treated chronically with antiretroviral therapy (ART), will develop progressive CD4 ϩ T-cell depletion and eventually succumb to AIDS. In contrast, the vast majority of naturally SIV-infected SMs maintain normal CD4 ϩ T-cell counts and live an apparently normal lifespan in captivity, [7][8][9] with only one report of classic AIDS to date. 10 It is important to note that the disease resistance of naturally SIV-infected SMs that show high levels of SIV viremia is substantially different from that of a rare subset of HIV-infected individuals defined as long-term nonprogressors, in whom viral replication is usually very lo...

Severe Depletion of Mucosal CD4+ T Cells in AIDS-Free Simian Immunodeficiency Virus-Infected Sooty Mangabeys

“…The most intriguing feature of naturally SIVinfected SMs is that, unlike HIV/SIV-infected humans and RMs, these animals typically remain asymptomatic and do not progress to AIDS despite levels of plasma viremia that are as high, or even higher, than those observed in HIV-infected patients (14,15). Although the mechanism(s) underlying the lack of disease progression in SMs is still unknown, our previous studies have shown that a characteristic feature of this infection is the overall preservation of peripheral blood (PB) CD4 ϩ T cell homeostasis that occurs in the absence of the chronic immune activation, bystander T cell apoptosis, and cell cycle dysregulation that are associated with pathogenic primate lentiviral infections (15)(16)(17)(18)(19).…”

Chronic innate immune activation as a cause of HIV-1 immunopathogenesis

“…Unfortunately, no information is available comparing IFN-α and IDO during acute infection in resistant versus susceptible primates. However, sooty mangabeys were reported to develop an adaptive cell-mediated response to SIV which is of lower magnitude than that observed in rhesus macaques or HIV-infected humans [76]. Because innate responses are pivotal in sustaining and enhancing the generation of T cell responses [10], it is possible that stronger activation of innate immunity occurs in the acute phase of SIV infection in rhesus macaques compared to sooty mangabeys (and HIV in humans compared to chimpanzees), thus leading to an apparently stronger adaptive T cell response.…”

Short Communication: HIV+ Viremic Slow Progressors Maintain Low Regulatory T Cell Numbers in Rectal Mucosa but Exhibit High T Cell Activation

“…Additionally, we observed low Treg numbers in the rectal mucosa of VSP, which may contribute to immune activation, but may also support stronger anti-HIV immune responses 31 and a preserved Treg:Th17 cell ratio. 32,33 Alternatively, it is possible that a blunted mucosal Treg response allows immune activation to persist without inhibiting normal T cell homeostasis, allowing the ongoing proliferation of CD4 + T cells despite high-level viremia. Despite increased frequencies of CD38 + PD-1 + and CD127 -T cells, VSP CD4s displayed reduced CD4 + T cell proliferation when stimulated ex vivo.…”