The major goal of this study is to develop and evaluate immunogens that mimic HIV-1 primary isolate envelopes and transitional envelope structures induced by the envelope/CD4 interaction. Two classes of immunogens derived from primary isolates YU-2 and DH012 will be tested for their ability to induce neutralizing antibodies against HIV-primary isolates. The first class will be recombinant monomeric gp120 and oligomeric gpl40. Our preliminary studies with the DH012 reagents indicate that antibodies could be induced which neutralize the homologous HIV-1 primary isolate (DH012). The second class of immunogens are CD4/envelope complexes which are meant to mimic transitional structures of HIV-1. It is hypothesized that this complex will expose new epitopes which might be sensitive to neutralizing antibody. This hypothesis will be evaluated through the use of a rhesus macaque soluble CD4 complexed with one of several envelope constructs. The preformed complexes will then be tested as immunogens in macaque for their ability to induce neutralizing antibody to both homologous and heterologous primary isolates. This concept has been previously studied by us and others but the experiments have always been complicated by the immunization of non-human species with human CD4. The results of such experiments have suggested a particularly strong antibody response to the xenogeneic CD4, and the observation that a large fraction of the virus blocking antibody responses are directed to CD4 rather than the virus. The work proposed here will circumvent this problem by matching the species source of the soluble CD4 with the species immunized - macaque in both cases. In this way we are hopeful that it will be fairly straightforward to determine whether or not immunization with the complex yields a significantly more potent and/or broader neutralizing response than does immunization with envelope alone. Such a result would reinforce the idea that certain neutralization sensitive epitopes of primary isolates are either masked, or not yet formed, on the resting envelope but do form and/or become exposed after binding to CD4.
| Zhu, C B; Zhu, L; Holz-Smith, S et al. (2001) The role of the third beta strand in gp120 conformation and neutralization sensitivity of the HIV-1 primary isolate DH012. Proc Natl Acad Sci U S A 98:15227-32 |
