Mucosal tissues constitute the major portals of entry for HIV-1. HIV-1 disease is often complicated by secondary mucosal infections in the intestine, lung, mouth, and genitourinary tract. Thus, efficacious vaccines to prevent primary HIV-l infection, as well as secondary opportunistic infections, will optimally include a protective immune response at mucosal sites. However, the mechanisms by which mucosal defenses are induced to protect against primary HIV-l infection are not well characterized. Moreover, identifying the mechanisms by which HIV1 compromises the induction of specific mucosal immune defenses is a critical area of basic investigation with relevant clinical implications. Specific antibody responses are initiated at inductive sites, such as intestinal Peyer's patches (PP), where the most efficient antigen-binding B cells are selected and activated. Following circulation through the blood, these cells home back to the effector sites, such as the lamina propria (LP) of the intestine, where they produce antibodies to exclude foreign antigens and pathogens from the internal milieu. In systemic lymph nodes, which are the inductive sites for systemic immune responses, HIV-l is sequestered by follicular dendritic cells (FDC) and causes extensive germinal center (GC) follicular hyperplasia early in disease, and later, involution with decay of cellular architecture. The integrity of GCs is critical for the development of antibody responses to T-dependent antigens. Whether HIV-l induces similar functional and anatomic defects in PP germinal centers is not known. The goal of this proposal is to characterize HIV-1-associated defects in B cells at different developmental stages (naive vs. differentiated) in the organized inductive sites (PP and nodules) of the intestine. This work will characterize the cellular structure of these areas with immunohistochemistry, the magnitude of HIV- I expression in these areas, and the genetic manifestations of intestinal B cell integrity by molecular analysis of VH genes. Moreover, the proposal will address whether sucessful treatment with HAART therapy will ameliorate these defects, and decrease the HIV-1 viral burden in mucosal inductive lymphoid tissue.
