The basic goal of this proposal is to understand the structural differences that exist between two highly related forms of the HIV glycoprotein that differ markedly in neutralization sensitivity through the use of chimeric env genes and antibody probes. The authors argue that the development of an effective and safe human immunodeficiency virus (HIV-1) vaccine would benefit greatly from an understanding of protective immune responses. In several animal models, including the infection of macaques with simian-human immunodeficiency viruses (SHIVs), neutralizing antibodies against the challenge virus can mediate protection. However, the applicants point out that two difficulties face the practical utilization of neutralizing antibodies for HIV-1 prophylaxis: a) the diversity of the HIV-1 envelope glycoproteins, the major target for neutralizing antibodies; and b) the relative resistance of primary HIV-1 isolates, compared with laboratory-adapted virus strains, to neutralization by antibodies. Although the major variable loops of the gp120 external envelope glycoprotein are known to contribute to these properties, understanding of the structure of these determinants lags behind that of more conserved envelope glycoprotein components. Results from the PI's laboratory have shown that in vivo passage of a SHIV bearing the envelope glycoproteins of a laboratory-adapted HIV-1 isolate, HXBc2, resulted in a virus that caused rapid CD4-positive T-lymphocyte depletion and AIDS in rhesus monkeys. A molecularly cloned virus, SHIV-HXBc2P 3.2, which contains the HIV-1 envelope glycoproteins of the passaged virus, was shown to be pathogenic in monkeys. The HXBc2P 3.2 envelope glycoproteins were markedly resistant to neutralization by soluble CD4 and several antibodies compared with the parental HXBc2 envelope glycoproteins. Thus, in vivo passage resulted in the acquisition of neutralization resistance typical of that of primary HIV-1 isolates.
The specific aims of this proposal are: 1. To create recombinants between the neutralization-sensitive HXBc2 and the neutralization-resistant HXBc2P 3.2 envelope glycoproteins to map the genetic determinants of resistance to neutralization by various antibodies. 2. To compare the structures of the parental and recombinant gp120 glycoprotein monomers by antibody cross-competition analysis. To study the structure of HIV-1 envelope glycoprotein trimers by antibody cross-competition analysis, and to characterize differences between HXBc2 and HXBc2P 3.2 envelope glycoprotein trimers.
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