HIV infection is associated with a slow progressive decline in CD4+ T cells and impairment of T and B cell functional responses which precedes the decline in CD4+ T cells. One of the proposed mechanisms for the decrease in T cell function has been attributed to the inhibitory effect of HIV envelope glycoproteins. there are two current hypotheses to explain the inhibitory effect of HIV envelope proteins gp120/160: i) by steric hindrance of CD4-MHC class II interaction and/or ii) by negative signaling via the CD4 molecule. The nature of the intracytoplasmic defects ensuing from either of the proposed mechanisms remain obscure. The central hypothesis of this proposal is that the HIV envelope glycoproteins can profoundly influence the intracytoplasmic signaling mechanisms of helper T lymphocytes, which could result in qualitative and quantitative decline in CD4+ T cells. A detailed examination of the effects of gp120 on signal transduction events related to CD3/TCR activation of T helper cells is being proposed, utilizing methodologies and concepts that are in the front line of research on T cell activation. An important and novel concept to be investigated is the nature of "partial" signaling occurring in gp120 treated CD4+ T cells by a CD4 independent pathway of TCR/CD3 signaling. The nature of CD4 mediated "positive" and "negative" signaling will also be analyzed. The roles of signaling mediated by soluble anti-CD4 mAb or gp120 and that of CD4 cross-linking followed by TCR activation in induction of either functional unresponsiveness (anergy) or activation induced cell death (apoptosis) will be investigated in a prototype "physiologic" cell culture system employing human T helper cell clones. Studies in patient peripheral blood T cells will be performed to determine if the defects observed in gp120 treated T cells in vitro are reproduced in the patients in vivo. The proposed investigations are important in gaining insights into AIDS pathogenesis, particularly in the context of the role of CD4 mediated signaling perturbations which could lead to qualitative and quantitative decline in CD4 T cells. Findings resulting from this study are potentially of significance for ongoing and planned vaccine strategies employing HIV envelope glycoproteins.