MODULATION OF PRIMARY HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 ENVELOPE GLYCOPROTEIN-MEDIATED ENTRY BY HUMAN-ANTIBODIES

Recently, we and others have shown that the interaction between envelo pe specific antibodies and primary human immunodeficiency virus type 1 (HIV-1) isolates may result in either inhibition or enhancement of vi rus entry. The outcome proved to be determined by the virus isolate ra ther than by the specificity of the antiserum used. To study the mecha nism underlying this phenomenon, a series of HIV-1 envelope glycoprote ins from closely related primary virus isolates of different syncytium inducing phenotypes, together with chimeras of these proteins, were t ested in an envelope trans-complementation assay for their sensitivity to either antibody mediated inhibition or enhancement of HIV-1 entry. Based on the observation that, in contrast to the inhibition of HIV-1 entry, antibody mediated enhancement was not temperature dependent an d could not be mediated by F(ab) fragments, we concluded that the mech anisms underlying these phenomena are different and that antibody medi ated enhancement of HIV-1 entry is largely if not exclusively mediated by HIV-1 glycoprotein cross-linking. The susceptibility of the envelo pe glycoprotein chimeric viruses to neutralization or enhancement of i nfectivity proved to be primarily determined by the configuration of t he V3 loop, and the affinity of the antibodies to monomeric HIV-1 gp16 0 molecules, proved to be of quantitative importance only. One human m onoclonal antibody directed against gp41 (IAM 2F5) inhibited entry of all the viruses studied, irrespective of their phenotype, and directly proportional to its affinity to monomeric HIV-1 gp160.