IMMUNE RESPONSE TO HIV SYNTHETIC PEPTIDES

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Human Immunodeficiency Virus (HIV), the causative agent of acquired immunodeficiency syndrome (AIDS), is a retrovirus which infects certain lymphocyte subpopulations and has been detected in central nervous system tissue of afflicted individuals. The virus is composed of a nucleocapsid core of protein and ribonucleic acid surrounded by a lipid envelope. This envelope contains 120,000 (gp 120) and 41,000 (gp 41) molecular weight glycoproteins, which are derived from the parent precursor 160,000 (gp 160) molecular weight glycoprotein. A major goal of the proposed study is to define antigenic regions of HIV envelope glycoproteins using synthetic peptides. Immunogenic peptides containing native determinants will be used to formulate complexes with protein carriers and adjuvant components in efforts to develop a synthetic vaccine protecting individuals from infection following challenge with infectious HIV. The initial mapping of the putative antigenic determinants of gp 160 derives from analysis of its primary amino acid sequence, which has been predicted from the envelope gene complementary DNA sequence. Computer algorithms will be used to predict possible epitopes associated with gp 160. They include Chou-Fasman prediction of protein secondary structural features and use of Hopp and Woods parameters in correlating antigenicity with sequential regions of high hydrophilicity. Envelope sequences from different known isolates will also be selected which are non-variant. Peptides will be assembled by solid phase methodology and coupled to protein carriers for inoculation of mice and rabbits. Anti-peptide antisera will be assayed for reactivity to peptide-protein conjugates along with intact envelope glycoproteins from cell lysates of disrupted, infected lymphocytes. Those peptides inducing anti-native responses to envelope glycoproteins will be selected as vaccine candidates, and their ability to induce an anamnestic response in mice will be assessed. These antisera will also be assayed for neutralization of HIV infectivity in vitro. A second panel of HIV envelope peptides will be screened for their ability to inhibit normal T- and B-cell proliferative responses toward external stimuli such as lymphokines and mitogens. This inhibition is characteristic of a general immunodepressive effect which has been established for other retroviral antigens. Peptides capable of inhibiting these responses will be investigated with respect to their potential interaction with membranes and membrane components of T- and B-cells.