This proposal focusses on the role of HIV in the pathogenesis of AIDS and AIDS-associated B-cell neoplasms. The proposed program project consists of six inter-related projects aimed at understanding the role of HIV in the etiology, pathogenesis and progression of AIDS and AIDS-associated cancers. We proposed to use the technique of site-directed mutagenesis to alter the aminoacid sequence of the envelope gene and test the resulting mutants for the abrogation of T4 binding, multinucleated giant cell formation and loss of T-cell cytotoxicity. We will also use several synthetic peptides homologous to the various domains of the envelope protein for their ability to block T4 binding or inhibit the ability of the virus to induce cell fusion. Synthetic peptides will also be used to map the antigenic sites on the envelope protein that are capable of inducing neutralizing antibody activity. Monoclonal antibodies raised against the synthetic peptides will in turn be used for the derivation of anti-idiotypic antibodies and their potential use as vaccines will be tested. To understand the role of other viral and cellular genes in the pathogenesis of AIDS, we will study the effect of CMV on HIV replication in vitro and in vivo. As a complement to the in vitro studies, HIV-infected infants, HIV-infected hemophiliac children and aymptomatic HIV-infected patients will be followed longitudinally to observe the effect of intercurrent CMV infection on the clinical course and replication of HIV. Finally, we will also investigate the role of cellular oncogenes, c-myc, bcl-1 and bcl-2 in the induction of virologists, geneticists, biochemists and clinicians with a common interest in the pathogenesis of AIDS.
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