The envelope glycoproteins are the principal targets for humoral immunity against HIV-1 infection, and are therefore a major focus of vaccine development. Although the envelope glycoproteins can be expressed as recombinant proteins that are immunogenic, it appears that these proteins are insufficient to provide protective immunity to HIV-1 infection. One contributing factor is the inability of envelope glycoproteins to elicit antibodies able to neutralize primary HIV-1 isolates with significant potency, despite their ability to induce antibodies able to neutralize T-cell line adapted strains. Despite the presence of neutralizing antibody epitopes on the recombinant proteins, the inefficiency with which antibodies against these epitopes are generated in humans may compromise the practical efficacy of these immunogens. Understanding the basis of these observations would facilitate the design of a new generation of immunogens that might better elicit antibodies effective against primary HIV-1 isolates. The principal investigator's approach to the problem is to gain a better understanding of the structure of the envelope glycoproteins, to learn how key neutralizing antibody epitopes are presented on these proteins. The methods he has chosen probe the topology of both monomeric and oligomeric forms of gp120 and gp160 with monoclonal antibodies against continuous and discontinuous epitopes that he is able to partially or totally define. He will study not only the envelope glycoproteins of T-cell line-adapted strains that were used in the first generation of subunit vaccines, but also proteins derived from primary isolates. As well as gp120 monomers, he will investigate the conformation of soluble gp160 molecules that contain the gp120 moiety linked to the ectodomain of gp41, because proteins of this type are under consideration as vaccine immunogens. He will also study the conformation of the envelope glycoproteins in their most native forms on the surfaces of virions and virus-infected cells. These studies are aimed at increasing our understanding of the antigenicity and immunogenicity of key viral proteins involved in the generation of humoral immunity against HIV-1, and may provide information to facilitate the development of new generations of HIV vaccines with improved performance.
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