HIV-1 ENV PROTEINS--TARGETS FOR ANTIVIRAL CHEMOTHERAPY

人类免疫缺陷病毒1型复制的任何步骤

Any step in replication of the human immunodeficiency virus type 1 (HIV-1) could potentially serve as a target for antiviral chemotherapy. Thus, antiviral agents could be aimed at HIV-1 proteins essential for virus replication, including viral structural and non-structural proteins and products of HIV-1 regulatory genes. Anti-HIV-1 chemotherapeutic agents targeted to HIV-1 reverse transcriptase and protease have been the most extensively investigated. Efforts to develop protective immunogens against HIV-1 resulted in the delineation of regions on env glycoproteins gpl2O and gp4l critical for infection. These regions include: the principal neutralizing determinant located on the V3 hypervariable loop of gpl2O; domains on gpl2O comprising the CD4 binding site; the fusion domain of gp41; and sites on gpl2O/gp4l involved in oligomerization of env glycoproteins, i.e., in virus assembly. These functionally important sites, recognizable by antibodies with appropriate specificity, represent also potential targets for chemotherapy. Indeed, compounds inhibiting the reaction between the V3 hypervariable loop and anti-V3 specific antibodies were discovered. The majority (about 67%) of substances inhibiting this antigen-antibody interaction also inhibited the replication of HIV-1 in both T-lymphocytic and promonocytic cell lines. Thus, a rapid prescreening method for compounds with anti-HIV-1 antiviral activity based on radioimmunoassays or enzyme-linked immunoadsorbent assays was discovered. Most of these compounds inhibited the reaction between V3 loops from distinct HIV-1 isolates (clones), differing greatly in primary amino acid sequence, and the corresponding antibodies. The goals of the proposed research are: (1) selection of additional antiviral compounds specific for the V3 hypervariable loop having (a) high antiviral activity against many HIV-1 isolates, and (b) low cytotoxicity; (2) Definition of structure-function relationships for compounds with antiviral activity directed against V3 loops, leading to the rational design of drugs with improved activity; (3) Demonstration of activity of these compounds against primary HIV-1 isolates in peripheral blood lymphocytes and monocytes; (4) Design of compounds with reactive groups leading to their irreversible binding to HIV-1 glycoproteins and thus to potentiation of antiviral activity; (5) Design of additional antiviral compounds targeted to regions on HIV-1 envelope glycoproteins other than the V3 loop; (6) Assessment of antiviral activity of these compounds when combined with antiviral drugs targeted to sites other than gpl2O/gp4l, for example, 3'-azido-2'-3'-dideoxythymidine (AZT); (7)To study in greater detail the effect of these compounds on steps in HIV-1 replication; (8) Search for the emergence of HIV-1 mutants resistant to the aforementioned compounds. Accomplishment of these goals is expected to lead to improved combined therapy, and possibly prophylaxis of HIV-1 infections.