Grant: Operating Grant - PA: HIV/AIDS Research Initiative - Biomedical/Clinical Stream

Immune response to infection is governed by cytokines secreted by various cells of the immune system. Cytokines have been classified into T helper (Th) type 1 and type 2 cytokines. Th1 cytokines promote cell mediated immune responses (CMIR) whereas Th2 cytokines mediate antibody responses. In HIV infection, the protective CMI responses diminish as disease progresses from the asymptomatic stage to the onset of AIDS. By down-regulating protective CMIR, HIV avoids an effective immune response resulting in progressive immunodeficiency and eventually the onset of AIDS related symptoms. We hypothesize that HIV infection disrupts the Th responses causing down regulation of Th1 cytokines such as IL-12, IL-23 and IL-27 (members of the IL-12 family of cytokines) thereby resulting in the loss of immune competence. An important key to elucidating the immune unresponsiveness associated with a profound down regulation of Th1 cytokines, therefore, lies in deciphering the molecular mechanism involved in this process. The mechanism by which IL-12, IL-23 and IL-27 production is regulated following infection of monocytic and dendritic cells is not clear at present. Our preliminary results suggest that the HIV regulatory gene products vpr and nef modulate Th1 cytokines production in LPS-stimulated human monocytic cells. In this research proposal, we will investigate the mechanisms by which the HIV regulatory proteins nef, tat and vpr down regulate the production of Th1 cytokines namely IL-12, IL-23 and IL-27 in monocytic and dendritic cells. The results of these studies will provide further insights into the molecular mechanisms by which HIV induces immunodeficiency. Understanding the signaling pathways in HIV-induced dysregulation of Th1 cytokines may allow the development of effective therapeutic strategies aimed at enhancing immune responsiveness and potentially eliminating virus from the tissue reservoirs in HIV infected individuals who receive potent anti-retroviral therapy.