The aim of this study is to investigate the mechanisms involved in immunologic hyporesponsiveness of lymphocytes from human deficiency virus (HIV) asymptomatic sero-positive, AIDS related complex (ARC) and AIDS, and whether it is due to an alteration in transmembrane signaling in those patients. The biochemical pathways involved in T-cell activation in response to specific and non-specific mitogens will be evaluated in lymphocytes from patients at different stages of infection. The patterns of secondary messenger response (IP3, CA++, cyclic AMP, cyclic GMP) and their relationship to phospholipase C and phosphatidylinositol hydrolysis and activation of protein kinase C will be determined. The relationship between secondary messenger response and immune parameters (including proliferative, interferon-gamma and IL-2 production) of the patients will be studied. The second messenger response will also be studied in a group of AIDS patients before and after 6 months of Zidovudine therapy. Transmembrane signaling in cell line cultures will also be studied in response to HIV infection. This approach will allow rare careful investigation of the effect of HIV on the biochemical pathways involved in transmembrane signaling. Cell lines supporting HIV replication will be used (H-9, MT-4, CEM and U937) and the response of both laboratory and fresh patient virus isolates will be evaluated. Understanding the HIV-induced, intracellular, physiological, and biochemical changes might allow manipulation of these responses to enhance the patient's immune response and the introduction of new anti-HIV agents that could offer novel therapeutic interventions.
