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

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.

Generation of the Pathogenic R5-Tropic Simian/Human Immunodeficiency Virus SHIV AD8 by Serial Passaging in Rhesus Macaques

“…It is also possible that SHIV AD8 infection of rhesus macaques negatively affects naïve CD4 ϩ T lymphocyte homeostasis in the thymus, thereby impeding the differentiation or emigration of this T cell subset. It has also recently been reported that the loss of naive CD4 ϩ T cells during SIVsmE543 infections was associated with the presence of autoreactive antibodies to CD4 ϩ T lymphocytes, platelets, double-stranded DNA, and phospholipid (27). Increased numbers of circulating IgG-coated CD4 ϩ T cells were observed in that study, and the levels of autoreactive antibodies were correlated with the extent of naïve CD4 ϩ T cell depletion.…”

Plasmacytoid Dendritic Cells Mediate Synergistic Effects of HIV and Lipopolysaccharide on CD27+IgD–Memory B Cell Apoptosis

“…HIV infection results in the increased apoptosis of gut epithelial cells and the depletion of Th17 cells, which permits MT from the damaged gut (50,51). As a consequence of MT, TLR ligands stimulate B cells and induce polyclonal activation, as reflected in the increased levels of auto-Abs in HIV infection (52). Our data show that TLR ligands also increase the sensitivity of mB cells to apoptosis through pDCs and IFN.…”

Conformational Epitope Consisting of the V3 and V4 Loops as a Target for Potent and Broad Neutralization of Simian Immunodeficiency Viruses

“…To analyze the induction of B404-like antibodies in SIV-infected macaques, Env-specific Fab clones were isolated from 4 SIVsmH635FC-infected macaques: H723, H704, H709, and H714 (26,39). Env-specific Fab clones from H723 were isolated from the previously constructed phage library (25) through panning against Env, which was conjugated by coating plate wells with the anti-Env Fab clones B404 (anti-gp120 conformational), B408 (anti-gp41 cluster I), and H301 (anti-gp120 V1).…”

“…The Fab library from SIVsmH635FC-infected rhesus macaque H723 was described previously (25). The Fab libraries from SIV-infected rhesus macaques H704, H709, H714, H711, and H725 (26,27,39) were similarly constructed using the pComb3X system according to the instructions of Barbas et al (40). Four macaques, H723, H704, H709, and H714, were infected with SIVsmH635FC.…”