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) appearance of immature/transitional B cells associated with advancing HIV-induced disease; 2) changes in B-cell populations associated with non-HIV immunodeficiencies; 3) mechanisms of B cell apoptosis associated with HIV disease; and 4) mechanisms of HIV virion trapping in lymphoid tissues. The first study describing the appearance of a population of immature/transitional B cells, defined by the expression of CD10, that is over-represented in HIV-infected individuals with advancing disease has been completed and published. Consistent with their immature status, these B cells were unresponsive to most B-cell stimuli, and their appearance was correlated with elevated serum levels of IL-7 and markers of HIV disease progression. In a more recent study, we reported on the expansion of immature/transitional B cells in the setting of a non-HIV immunodeficiency involving idiopathic CD4+ T cell lymphopenia (ICL), and concluded that homeostatic compensation associated with lymphopenia is likely to be the underlying explanation for the appearance of immature/transitional B cells in ICL patients and in HIV-infected individuals with advancing disease. In the most recent ongoing study, we have investigated mechanisms of apoptosis in two distinct B-cell populations found to be 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 that is accompanied by high levels of activated Bak and Bax. High induction of activated Bax and Bak is consistent with a prominent role for mitochondria in intrinsic apoptosis. In contrast, CD10-/CD21lo mature/activated B cells express high levels of CD95, rendering them highly susceptible to CD95L-mediated apoptosis, an extrinsic pathway that is less dependent on the mitochondria than the intrinsic pathway. In one notable exception to current paradigms on apoptosis, we find that while caspase-8 is involved in the extrinsic apoptotic pathway, as predicted from current models, it also plays a role in the intrinsic apoptosis of immature/transitional B cells. Finally, we continue to pursue investigations of extracellular HIV reservoirs in a mouse model and have demonstrated that the complement receptor CD21 is essential for virion trapping in lymphoid tissues and that anti-CD21 antibodies that can displace HIV from CD21 positive cells have the potential for reducing viral burdens in vivo.