Over the past year we have pursued studies on B lymphocyte immunopathogenesis in HIV disease by focusing on 1) functional defects of B cells associated with ongoing viral replication, 2) the genotypic and phenotypic correlates of B cell dysfunction, and 3) mechanisms of HIV virion trapping in lymph nodes. Two projects were completed on the deleterious effects of HIV plasma viremia on B cell function, the first demonstrating that B cells of viremic patients have a poor response to CD4+ T cell help and the second demonstrating that the costimulatory function of B cells of viremic patients is defective. The low responsiveness of B cells to CD4+ T cell help was associated with an inadequate induction of the IL-2 receptor CD25 on B cells, leading to reduced response to IL-2 secreted by the effector CD4+ T cells. In the second functional study, the defect in B cell costimulatory function towards CD4+ T cells was found to be associated with an excessive expression of costimulatory molecules CD80 and CD86 in vivo and a depressed induction in vitro following B cell activation through the B cell receptor and CD40. A third project was initiated as a follow-up to the study showing a reduced B cell responsiveness to IL-2 in viremic patients. We have pursued this investigation by comparing B cell response to B cell receptor stimulation in the presence of either IL-2 or IL-4. We are finding that while responses to IL-2 are defective in viremic patients, responses to IL-4 are normal. The underlying mechanisms and implications for antibody responses are currently being investigated. More recently, genotypic (DNA microarray) and phenotypic studies have shown that HIV viremia is associated with numerous abnormal B cell gene expression patterns, confirming and extending the previous findings that HIV-induced B cell hyperactivation leads to terminal differentiation. These genotypic and phenotypic findings include the demonstration that HIV viremia induces increased levels of Fas and perturbs the expression of B cell survival receptors of the TNF superfamily. Current efforts are underway to establish the functional relevance of these latest observations. Finally, mechanisms of HIV trapping in lymph nodes are being studied through a mouse model. Preliminary findings indicate that the complement receptor 2 or CD21 is required for virion trapping and that contrary to current dogma, immunoglobulins but not necessarily anti-HIV immunoglobulins are also required for virion trapping. Current efforts are underway to confirm these observations using various transgenic and knockout mice.