We propose to elucidate the host immune response in HIV-infected Hispanic individuals by a study of specific T cell subsets dominant in the disease course; and seek mechanisms that lead to suppression of T cell activation as well as mechanisms that enhance T cell responses via N-acetylcysteine (NAC). Specific objectives address three hypotheses: 1) that the T cell phenotypes which dominate the CD4+ and CD8+ populations may change drastically during the course of the disease; 2) that the Nef HIV protein is a causative agent for suppression of both CD4+ and CD8+ T cell activation and mitogenesis; and 3) N-acetylcysteine (NAC) may regulate HIV expression and T cell responses to mitogenesis in AIDS T cells by regulating nuclear factor NF-kB . Specific CD4+ and CD8+ phenotypes, isolated with a cell sorter, will be tested for mitogenic response using anti-CD3, ConA, pokeweed mitogen, and enterotoxin activation with both PMA (phorbol ester) and anti-CD28 costimulation in order to assess the activation potential. Likewise, CD4+ and CD8+ normal cells, made NEF= or NEF- with chimeric virus (HBX-2) by electroporation, will also be studied for mitogenic response, cytokine production (IL-4), and p24 viral protein in order to assess negative or positive effects of Nef protein on T cell activation. Also, CD4+ and CD8+ cells from severely suppressed AIDS blood will be tested for nuclear factors NfkB, AP-1. etc., that regulate mRNA production for may cytokines. Nuclear factors will also be quantitated in special phenotypic subsets and NEF+ cells. In all cases where suppression is observed, reversal with N-acetylcysteine (NAC), which enhances IL-2 production and NF-kB, will be studied. This work should bridge gaps in our knowledge of mechanisms that control suppression and activation of T Cell subsets in AIDS, and lead to a better picture of AIDS pathogenesis, and vulnerable points for drug intervention and clinical manipulation, especially in the Hispanic population. It will put our understanding of NAC, as it relates to AIDS, on a more secure basis, and made more timely by a clinical study currently underway at Stanford University, Palo Alto, CA., on the effect of NAC administered to AIDS patients.
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