The long-term objective of this project is to develop antibodies and anti-idiotypic antibodies targeting the relatively conserved core structure of gp4l as prophylactic and therapeutic strategies blocking HIV-1 entry. Synthetic peptides N36 and C34, corresponding to the relatively conserved sequences of the N and C-terminal coiled-coil regions of gp4l, have been shown each to inhibit HIV-1 env-mediated membrane fusion and, upon mixing at equimolar concentration, form a stable alpha-helical trimer of heterodimers, representing the fusion-active conformational core structure of gp4l. The specific aims of this project are: 1) to generate polyclonal antibodies against N36, C34 and the N36/C34 complex, in order to determine whether or not the antibodies recognize the tertiary and quaternary structure of the corresponding relatively conserved regions in gp4l, interact with the fusion-active conformational core domain, and inhibit HIV-1 infection; 2) to induce polyclonal and monoclonal anti-idiotypic antibodies against IgG antibodies to N36, C34 and the N36/C34 complex, in order to determine whether or not the anti-idiotypic antibodies mimic the functions of these peptides and inhibit HIV-1 env-mediated membrane fusion; and 3) to utilize these antibodies and anti-idiotypic antibodies to study the mechanism of peptide-mediated inhibition of membrane fusion initiated by HIV-1.