The overall goal of this revised application is to examine cellular anti-HIV-1 cytolytic reactivities, with particular emphasis on viral envelope specificities, in order to identify those elements which may comprise a beneficial or protective versus a pathogenic immune response. A number of different priming strategies will be used in attempts to elicit MHC class I- and class-II restricted anti-HIV-1 CTL in cultures of PBMC established from seronegative donors. A portion of these studies will focus on possible allotype restriction of anti-peptide reactivities. Cell-mediated anti-viral cytotoxicities elicited in response to HIV-1 infection will be characterized with respect to antibody-directed K-cell-mediated versus CTL activities present in patients at various stages of disease as well as during disease progression in a series of longitudinal studies over an extended time course. In addition to utilizing vaccinia/HIV-1 construct infected autologous B-cell targets, cytolytic reactivities will also be measured against a panel of highly relevant target cell populations representative of viral reservoirs including HIV-1 infected T-cells, B-cells, monocytes and macrophages. Possible destructive CTL reactivities will be assessed on non-infected antigen presenting cells (APC) which have been assessed on non-infected antigen presenting cells (APC) which have been pulsed with various HIV-1 gene products with special emphasis on CD4+ cells which can bind, process and present target determinants from native gp120. Lastly, efforts will be made to determine what role CD4+ CTL may play in controlling or contributing to disease progression.
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