IDENTIFICATION OF CD4 AND MAJOR HISTOCOMPATIBILITY COMPLEX FUNCTIONALPEPTIDE SITES AND THEIR HOMOLOGY WITH OLIGOPEPTIDES FROM HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 GLYCOPROTEIN GP120 - ROLE IN AIDS PATHOGENESIS

CD4 molecules interact with class II major histocompatibility complex molecules as a critical costimulatory signal in CD4+ cell immune activ ation. CD4 also recognizes a specific region of the human immunodefici ency virus type 1 (HIV-1) envelope glycoprotein gp120 forming a bindin g site for early stages of HIV-1 infection. We designed two software p ackages, AUTOMAT and CRITIC, Which allowed us to identify similarities between regions of HIV-1 proteins and immunoregulatory protein sequen ces stored in data banks. In this report we have characterized (i) a p entapeptide, SLWDQ, found in both CD4 and HIV-1 gp120, which surprisin gly had remained undetected in these two well-studied molecules until now, and (ii) an HLA sequence corresponding to the putative functional site of H2 I-A. We found that a region of gp120 (residues 254-263) kn own to be similar to a sequence in HLA class II beta chain overlaps th is functional region. We showed experimentally that these two CD4 and HLA peptide segments inhibit CD4+ cell immune activation. There is str ong inhibition (50% up to 80%) of immune activation by SLWDQ-containin g gp120 segments and a lesser inhibition by the gp120 HLA-homologous s egment. In addition, we found that SLWDQ induced in HIV-1-infected ind ividuals a humoral (antibody) and cellular (cytotoxic T lymphocyte) im mune reaction. We propose that these HIV-1 gp120 segments, together wi th the known CD4-binding region, may contribute to the HIV-1-induced i mmunosuppression by two mechanisms affecting CD4-HLA interaction durin g T-cell immune activation: autoimmune reaction toward CD4 and direct interference with the CD4-HLA costimulatory signal inducing CD4+ cell anergy with, as a consequence, generation of immunosuppression.