Association of Progressive CD4+ T Cell Decline in SIV Infection with the Induction of Autoreactive Antibodies

Takeo Kuwata,Jason M Brenchley,Vanessa M Hirsch,Sonya Whitted,Ilnour Ourmanov,Alicia Buckler-White,Ranjini Iyengar,Charles R Brown,Que Dang,Yoshiaki Nishimura,Michael Farzan

doi:10.1371/journal.ppat.1000372

Takeo Kuwata, Jason M Brenchley + Show 9 more

Open Access

https://doi.org/10.1371/journal.ppat.1000372

Copy DOI

Abstract

The progressive decline of CD4+ T cells is a hallmark of disease progression in human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infection. Whereas the acute phase of the infection is dominated by virus-mediated depletion of memory CD4+ T cells, chronic infection is often associated with a progressive decline of total CD4+ T cells, including the naïve subset. The mechanism of this second phase of CD4+ T cell loss is unclear and may include immune activation–induced cell death, immune-mediated destruction, and regenerative or homeostatic failure. We studied patterns of CD4+ T cell subset depletion in blood and tissues in a group of 20 rhesus macaques inoculated with derivatives of the pathogenic SIVsmE543-3 or SIVmac239. Phenotypic analysis of CD4+ T cells demonstrated two patterns of CD4+ T cell depletion, primarily affecting either naïve or memory CD4+ T cells. Progressive decline of total CD4+ T cells was observed only in macaques with naïve CD4+ T cell depletion (ND), though the depletion of memory CD4+ T cells was profound in macaques with memory CD4+ T cell depletion (MD). ND macaques exhibited lower viral load and higher SIV-specific antibody responses and greater B cell activation than MD macaques. Depletion of naïve CD4+ T cells was associated with plasma antibodies autoreactive with CD4+ T cells, increasing numbers of IgG-coated CD4+ T cells, and increased incidence of autoreactive antibodies to platelets (GPIIIa), dsDNA, and phospholipid (aPL). Consistent with a biological role of these antibodies, these latter antibodies were accompanied by clinical features associated with autoimmune disorders, thrombocytopenia, and catastrophic thrombotic events. More importantly for AIDS pathogenesis, the level of autoreactive antibodies significantly correlated with the extent of naïve CD4+ T cell depletion. These results suggest an important role of autoreactive antibodies in the CD4+ T cell decline observed during progression to AIDS.

Highlights

Progressive CD4+ T cell decline in human immunodeficiency virus (HIV) infection, the slow but persistent loss of both naıve and memory CD4+ T cells [1,2,3], is an important marker of progression to AIDS
Mechanisms related to the intense immune activation, a hallmark of HIV infection, were proposed
We found that animals that exhibited slow, progressive loss of CD4+ T cells had circulating antibodies that reacted with CD4+ T cells and that the levels of these antibodies correlated with the extent of CD4+ T cell depletion

Summary

Introduction

Progressive CD4+ T cell decline in human immunodeficiency virus (HIV) infection, the slow but persistent loss of both naıve and memory CD4+ T cells [1,2,3], is an important marker of progression to AIDS. The mechanism of chronic CD4+ T cell depletion is not clear since the number of infected cells at any one point in time would not seem to account for the extent of CD4+ T cell loss Such progressive decline in CD4+ T cells is observed in some but not all simian immunodeficiency virus (SIV) macaque models for AIDS [4,5,6]. SIV infection of natural host species, such as sooty mangabeys and African green monkeys, is not associated with the abnormal chronic immune activation and the accelerated T cell turnover seen in pathogenic models, suggesting a critical role of immune activation in the pathogenesis of AIDS [23,24]

Methods

Results

Discussion

Conclusion