DEVELOPMENT OF IMMUNOREGULATORY PEPTIDES FOR AIDS

THE NEED TO DEVELOP EFFECTIVE IMMUNOREGULATORY OR ANTIVIRAL REAGENTS THAT WILL CONTROL HIV INFECTION IS PARAMOUNT. IN STUDIES OF THE CD4 ATTACHMENT SITE ON THE HIV ENVELOPE, A SYNTHETIC PEPTIDE THAT MAY BE A STRONG CANDIDATE THERAPEUTIC AGENT HAS BEEN IDENTIFIED. THE PEPTIDE, TERMED A25D, REPRESENTS AN 18-AMINO ACID SEQUENCE FROM THE PUTATIVE CD4 ATTACHMENT SITE ON GP120, AND BIOPHYSICAL COMPARISONS SUGGEST THAT IT CONTAINS BOTH B- AND T-CELL EPITOPES. A25D BLOCKS HIV TRANSMISSION IN VITRO AS DETERMINED IN A STANDARD SYNCYTIAL FORMATION ASSAY; HOWEVER, STUDIES PERFORMED ON HIV-INFECTED INDIVIDUALS INDICATE THAT BOTH B- AND T-CELL RESPONSES TO THE PEPTIDE ARE MINIMAL. THESE FINDINGS SUGGEST THAT ALTHOUGH A25D MAY REPRESENT A CRITICAL EPITOPE ON THE HIV BINDING SITE CAPABLE OF INDUCINGGROUP-SPECIFIC NEUTRALIZATION, THIS POTENTIAL IS NOT REALIZED IN MOST INDIVIDUALS BECAUSE THE HIGHLY IMMUNODOMINANT REGIONS OF THE ENVELOPE ESTABLISH A CLONAL DOMINANCE AND SUPPRESS EFFECTIVE RESPONSES TO THE ATTACHMENTSITE. PHASE I WILL EXAMINE THE POTENTIAL UTILITY OF A25D AND RELATED PEPTIDES AS AGENTS TO PROMOTE ACTIVE ANTI-HIV IMMUNITY. THE ABILITY OF THE MATERIAL TO INDUCE ANTI-GP120 RESPONSES IN MICE AND RABBITS WILL BE TESTED. FURTHERMORE, A25D AND RELATED SYNTHETIC AND RECOMBINANT PEPTIDES WILL BE USED TO SCREEN AND CHARACTERIZE THE SERA OF HIV-INFECTED INDIVIDUALS AND SIV-INFECTED MACAQUES FOR VIRUS-NEUTRALIZINGANTIBODIES. THEIR ABILITY TO STIMULATE VIRION PRODUCTION BY STIMULATING INFECTED LYMPHOCYTES WILL ALSO BE DETERMINED.