Role of B Lymphocytes In HIV Infection And Pathogenesis

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Abstract

Over the past year we have pursued studies on B lymphocyte immunopathogenesis in the setting of HIV disease by focusing on 1) mechanisms of immature/transitional B-cell over-expression in advancing HIV disease; 2) mechanisms of B-cell apoptosis associated with HIV disease; 3) changes in B-cell counts and subpopulations that occur following initiation of antiretroviral therapy (ART); and 4) mechanisms of HIV virion trapping in lymphoid tissues. The first study addressing mechanisms of immature/transitional B-cell expansion in the setting of HIV disease has been completed and in part published in Blood. The appearance of these cells has been associated with elevated serum levels of IL-7 and decreased CD4+ T cell counts in both HIV disease and a non-HIV immunodeficiency disease called idiopathic CD4+ T cell lymphopenia (ICL). These observations led to the conclusion that homeostatic compensation associated with CD4+ T cell lymphopenia is likely to be the underlying cause of the expansion of immature/transitional B cells in ICL patients and in HIV-infected individuals with advancing disease. [unreadable] In a second related study, published in the Proceedings of the National Academy of Sciences, we demonstrated distinct mechanisms of apoptosis in the two major B-cell populations expanded in HIV-infected individuals with active disease, namely CD10+ immature/transitional and CD10-/CD21lo mature/activated B cells. Our findings indicate that CD10+ immature/transitional B cells express reduced levels of the pro-survival members of the Bcl-2 family, rendering them highly susceptible to intrinsic apoptosis. In contrast, CD10-/CD21lo mature/activated B cells express high levels of CD95, rendering them highly susceptible to CD95 ligand-mediated apoptosis, an extrinsic pathway of apoptosis. In a third related study, currently under final review in the Journal of Infectious Diseases, we demonstrate that the over-expression of the two aforementioned B-cell subpopulations in HIV-infected individuals with active disease is reversed with effective ART. Effective ART also leads to a normalization of B-cell counts, suggesting that ongoing HIV replication is associated with a net loss of B cells, possibly through mechanisms such as increased intrinsic and extrinsic apoptosis. Finally, in a fourth study published in the Journal of Immunology, we investigated extracellular HIV reservoirs in a mouse model. Our findings indicate that the complement receptor CD21 is essential for HIV virion trapping in lymphoid tissues and that anti-CD21 antibodies can displace HIV bound to CD21-expressing cells, thus providing a potential therapeutic approach for reducing viral burdens in vivo.