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

Barry, Ashley P.; Silvestri, Guido; Safrit, Jeffrey T.; Sumpter, Beth; Kozyr, Natalia; McClure, Harold M.; Staprans, Silvija I.; Feinberg, Mark B.

doi:10.4049/jimmunol.178.12.8002

Cited by 66 publications

(75 citation statements)

References 62 publications

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“…The fact that SMs maintain high viral load indicates that the disease resistance of these animals is unlikely to be because of particularly strong SIVspecific CTL responses. This hypothesis is also supported by the observations that SIV-infected SMs have lower levels of virus-specific T cell responses than do HIV-infected individuals (13) and that depletion of CD8 + T cells does not result in any significant increase in virus replication (14). Similar to pathogenic models of HIV/SIV infection (15)(16)(17)(18), more than 90% of SIVsmm replication in naturally SIV-infected SMs occurs in short-lived cells, which suggests that activated CD4 + T cells are the major site for viral replication (19).…”

Section: Introductionsupporting

confidence: 71%

Availability of activated CD4+ T cells dictates the level of viremia in naturally SIV-infected sooty mangabeys

et al. 2008

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Naturally SIV-infected sooty mangabeys (SMs) remain asymptomatic despite high virus replication. Elucidating the mechanisms underlying AIDS resistance of SIV-infected SMs may provide crucial information to better understand AIDS pathogenesis. In this study, we assessed the determinants of set-point viremia in naturally SIV-infected SMs, i.e., immune control of SIV replication versus target cell limitation. We depleted CD4 + T cells in 6 naturally SIV-infected SMs by treating with humanized anti-CD4 mAb (Cdr-OKT4A-huIgG1). CD4 + T cells were depleted almost completely in blood and BM and at variable levels in mucosal tissues and LNs. No marked depletion of CD14 + monocytes was observed. Importantly, CD4 + T cell depletion was associated with a rapid, significant decline in viral load, which returned to baseline level at day 30-45, coincident with an increased fraction of proliferating and activated CD4 + T cells. Throughout the study, virus replication correlated with the level of proliferating CD4 + T cells. CD4 + T cell depletion did not induce any changes in the fraction of Tregs or the level of SIV-specific CD8 + T cells. Our results suggest that the availability of activated CD4 + T cells, rather than immune control of SIV replication, is the main determinant of set-point viral load during natural SIV infection of SMs.

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Section: Introductionsupporting

confidence: 71%

Availability of activated CD4+ T cells dictates the level of viremia in naturally SIV-infected sooty mangabeys

et al. 2008

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“…Indeed, the level of SIV-specific T cell responses in SMs is comparable to that in RMs and is neither stronger nor broader than what has been found during pathogenic HIV/SIV infections (24)(25)(26). Furthermore, depletion of CD8 + T cells in SMs was found to be followed by minor changes in SIV replication in the only published Understanding the benign nature of SIV infection in natural hosts study at this writing (27). From a vaccine perspective, the fact that the AIDS resistance of natural SIV hosts appears to be independent of effective control of virus replication emphasizes the tremendous challenge of artificially inducing, via immunization, a type of protective immunity that has not been selected for through many thousand years of evolutionary pressure posed by lentiviruses on the primate immune system.…”

Section: Basic Features Of Natural Siv Infectionmentioning

confidence: 81%

Understanding the benign nature of SIV infection in natural hosts

et al. 2007

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In striking contrast to HIV infection, natural SIV infection of African nonhuman primates is asymptomatic and usually does not induce significant CD4 + T cell depletion despite high levels of virus replication. Recently, significant progress has been made in understanding the mechanisms underlying the remarkable difference in infection outcome between natural and nonnatural HIV/ SIV hosts. These advances include the identification of limited immune activation as a key factor protecting natural SIV hosts from AIDS and the discovery of low CC chemokine receptor 5 expression on CD4 + T cells as a specific and consistent immunologic feature in these animals. Further elucidation of the pathways by which the differences in immune activation between natural and nonnatural hosts are manifest holds promise for the design of novel therapeutic approaches to HIV infection.Nonstandard abbreviations used: AGM, African green monkey; CCR5, CC chemokine receptor 5; CXCR4, CXC chemokine receptor 4; LTNP, long-term nonprogressor; MALT, mucosa-associated lymphoid tissue; NHP, nonhuman primate; RM, rhesus macaque; SM, sooty mangabey.

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“…The observed relative AIDS resistance of naturally SIV-infected sooty mangabeys seems to be mostly independent of the virus-specific CD8 ϩ T-cell response, as transient monoclonal antibody (MAb)-induced depletion of cytotoxic CD8 T cells in infected sooty mangabeys resulted in only minor changes in the levels of plasma viremia (2). In addition, the magnitude of SIV-specific CD8 T-cell responses in SIV-infected mangabeys is markedly reduced compared to HIV-infected humans (7).…”

mentioning

confidence: 99%

The Quality of Chimpanzee T-Cell Activation and Simian Immunodeficiency Virus/Human Immunodeficiency Virus Susceptibility Achieved via Antibody-Mediated T-Cell Receptor/CD3 Stimulation Is a Function of the Anti-CD3 Antibody Isotype

Bibollet-Ruche¹,

McKinney

Duverger³

et al. 2008

J Virol

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While human immunodeficiency virus type 1 (HIV-1) infection is associated with hyperimmune activation and systemic depletion of CD4؉ T cells, simian immunodeficiency virus (SIV) infection in sooty mangabeys or chimpanzees does not exhibit these hallmarks. Control of immune activation is thought to be one of the major components that govern species-dependent differences in the disease pathogenesis. A previous study introduced the idea that the resistance of chimpanzees to SIVcpz infection-induced hyperimmune activation could be the result of the expression of select sialic acid-recognizing immunoglobulin (Ig)-like lectin (Siglec) superfamily members by chimpanzee T cells. Siglecs, which are absent on human T cells, were thought to control levels of T-cell activation in chimpanzees and were thus suggested as a cause for the pathogenic differences in the course of SIVcpz or HIV-1 infection. As in human models of T-cell activation, stimulation had been attempted using an anti-CD3 monoclonal antibody (MAb) (UCHT1; isotype IgG1), but despite efficient binding, UCHT1 failed to activate chimpanzee T cells, an activation block that could be partially overcome by MAb-induced Siglec-5 internalization. We herein demonstrate that anti-CD3 MAb-mediated chimpanzee T-cell activation is a function of the anti-CD3 MAb isotype and is not governed by Siglec expression. While IgG1 anti-CD3 MAbs fail to stimulate chimpanzee T cells, IgG2a anti-CD3 MAbs activate chimpanzee T cells in the absence of Siglec manipulations. Our results thus imply that prior to studying possible differences between human and chimpanzee T-cell activation, a relevant model of chimpanzee T cell activation needs to be established.

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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

Cited by 66 publications

References 62 publications

Availability of activated CD4+ T cells dictates the level of viremia in naturally SIV-infected sooty mangabeys

Availability of activated CD4+ T cells dictates the level of viremia in naturally SIV-infected sooty mangabeys

Understanding the benign nature of SIV infection in natural hosts

The Quality of Chimpanzee T-Cell Activation and Simian Immunodeficiency Virus/Human Immunodeficiency Virus Susceptibility Achieved via Antibody-Mediated T-Cell Receptor/CD3 Stimulation Is a Function of the Anti-CD3 Antibody Isotype

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