An approach for development of new drugs for AIDS which inhibit the novel receptor for AIDS virus

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Infection by human immunodeficiency virus (HIV) is due to virus-cell fusion mediated by interaction of the envelope glycoprotein gp120 of HIV with the CD4 molecule present on the surface of T4^+ lymphocytes. However, the CD4 molecule may not be the only component of HIV receptor because mouse cells expressing the human CD4 molecule are not infected by HIV. We recently found a novel membrane-bound serine protease, named tryptase TL2, other than CD4 receptor in human T4^+ lymphocytes which specifically binds V3 domain of HIV gp120. The V3 domain has been reported to be the principal neutralizing determinant of HIV and also to be a determinant for cellular tropism of HIV infection. Scatchard analysis revealed a single class of gp120 binding site on tryptase TL2 with an apparent dissociation constant of 3.8 x 10^<-8> M for tryptase TL2.In order to find the compound(s) which effectively inhibit the binding of gp120 to tryptase TL2, we have analyzed the effect of various Kunitztype protease inhibitors with the sequence GPCR in their active site and synthetic V3 domain peptides with the sequence GPCR in their center, which correspond to the principal neutralizing epitopes of gp120 of various HIV strains and of antibody against tryptase TL2. The results show that trypstatin, Kunitz type protease inhibitor, and antibody against tryptase TL2 effectively inhibited the binding of gp120 to tryptase TL2. They also inhibited syncytia formation induced by HIV. Although V3 domain is a hypervariable region, tryptase TL2 may be a common binding receptor in the membrane of T lymphocytes for various V3 domain of HIV strains. These results suggest that trypstatin and the antibody against tryptase TL2 may be useful for therapeutic treatment for AIDS. The studies on DNA cloning of trypstatin and its expression in E. Coli are now in progress. Further studies are need to confirm the effect of these compounds on HIV infection in vivo and in vitro