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

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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. Despite intensive study, the mechanisms of CD4+ T cell depletion in human immunodeficiency virus (HIV) infection remain elusive. The identification of the CD4 receptor as the primary receptor for HIV seemed initially to explain the loss of CD4+ T cell lymphocytes in AIDS. However, the number of infected cells at any point in time is insufficient to explain the extent of loss and the slow disease course. While virus-induced cell death might explain early loss of CD4+ T cells, such mechanisms were unlikely to explain the slow depletion over the long period leading to AIDS. Thus, mechanisms related to the intense immune activation, also a hallmark of HIV infection, were proposed. Here, we studied a surrogate model for AIDS, simian immunodeficiency (SIV) infection of rhesus macaques, to explore the mechanisms of this second phase of depletion. 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. These results suggest that autoimmune destruction of CD4+ T cells represents a valid mechanism to explore in the pathogenesis of CD4+ T cell loss in AIDS.

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