AIDS is caused by infection of T4 lymphocytes and macrophages by a human retrovirus, designated as HTLV-III/LAV/HIV virus. We hypothesized that the immune deficiency in AIDS may be in part due to lysis of these critical cells of the immune system by HTLV- III specific, HLA-restricted cytotoxic T lymphocytes (CTL). The definition of CTL responses to HTLV-III virus-infected cells is needed for an improved understanding of the pathogenesis and for optimal approaches at therapy and prevention of AIDS. HTLV-III specific CTL responses will be assessed using as target cells HTLV-III Infected HLA-typed T4+ cell lines. The presence of HTLV-III specific memory CTL in antibody positive subjects will be determined following secondary stimulation in vitro with HTLV-III infected autologous antigen presenting cells. The virus specificity of the MHC-restricted HTLV-III specific CTL will be assessed on target cells infected with various strains of HTLV-III virus, HTLV-I, influenza or herpes simplex virus. It is known that viral specific MHC-restricted CTL recognized epitopes which differ from those recognized by antibodies. We will determine the epitopes recognized by the HTLV-III specific CTL utilizing subvirion peptides to stimulate memory CTL responses and to define the epitopes on target cells recognized by HTLV-III specific CTL. The HLA restriction of HTLV-III specific CTL will be assessed to determine if they are restricted by Class I or Class II antigens and if HLA haplotype preference of peptide or virus induced CTL occurs. Clones of HTLV-III specific human CTL will be developed to analyze the specificity of the virion antigens which induce CTL. The CTL clones will also be used to examine the evolutionary pressure of CTL on HTLV-III virus antigenic variations by subjecting T4+ virus-infected cells to repeated challenge with a CTL clone to determine if CTL resistant infected cells emerge. Clinical investigations will be performed to correlate the clinical stages of HTLV-III infection with the level of HTLV-III specific CTL responses, and to assess the induction of HTLV-III specific memory CTL responses following administration of experimental vaccines. The results of the proposed studies should provide basic insights into the interaction between HTLV-III virion epitopes and HLA-restricted HTLV-III virus specific human CTL, and provided an improved understanding of the pathogenesis and the prevention of AIDS by immunization.
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