Several years ago, we and others demonstrated that lymph nodes are a major reservoir for human immunodeficiency virus (HIV) and a major site of active virus replication in infected individuals. Subsequent studies from our group showed that virologic cross talk between B cells and CD4+ T cells occurs within the microenvironment of lymphoid tissues (LT), and that immunosuppressive CD25+CD4+ regulatory T (Treg) cells enriched in the LT. Furthermore, Treg cells isolated from the LT are particularly effective in suppressing HIV-specific cytolytic activity. More recently, follicular helper (Tfh) CD4+ T cells have been described in LT and found to play an important role in providing help to B cells during germinal center reactions. These Tfh cells are expanded in HIV-infected viremic individuals and their numbers correlate with frequencies of germinal center B cells, consistent with longstanding observations of HIV-induced GC hyperplasia in untreated infected individuals. Despite the increased frequencies of Tfh and GC B cells in LT, there is also evidence for reduced immune function due to over-expression of negative regulatory molecules. We are currently investigating several issues related to the impact of HIV infection/replication on the immune competence and homing profiles of numerous cell types within the LT. Given the paucity of Tfh and GC B cells in the peripheral blood, these studies are more appropriately conducted with tissue samples. We will also pursue immunological, migrational and virologic characteristics of various cell types including B cells and their subsets and CD4+, CD8+ and NK cells in the LT and bone marrow (BM) tissue. In this regard, the BM is both the site of B-cell development and the only known long-lived repository of plasma cells that are responsible for maintaining humoral immunity. While HIV infection has been shown to impair hematopoiesis in the BM, relatively little is known regarding the effect of HIV infection on plasma cells that home back to the BM after maturation.