Infection with the human immunodeficiency virus type1 (HIV-1) leads to the acquired immunodeficiency syndrome (AIDS). Only a few HIV-1-infected people produce antibodies that neutralize a broad range of HIV-1 strains. These are mainly produced by long-term non-progressers; people, who have been infected for years, but have never developed the signs and symptoms of AIDS. These neutralizing antibodies are mostly against the envelope proteins of the virus, gpl20, gp41 and their precursor gpl60; three such human antibodies have been cloned, bl2, 2F5 and 2G12. In contrast, the antibodies produced by most HIV-1-infected people (which include antibodies against the envelope proteins) do not kill the virus or virus-infected cells from different strains of HIV-1. The applicants propose to find leads for a vaccine against HIV-1 infection that would induce the production of neutralizing antibodies against a broad spectrum of HIV-1 strains. They will use the monoclonal, HIV-1-neutralizing antibodies bl2, 2F5 and 2G12 to screen a panel of 15-20 peptide libraries. Each library in the panel contains 200-million to 1-billion different molecules, and the peptides in each library have a different predominating shape. Thus, the applicants will search a large variety of sequences and structures to find peptides that bind neutralizing antibodies to HIV-1. They will test these peptides for their ability to induce the production of HIV-1-cross-reactive antibodies by a number of immunization strategies, and will then test immune sera for the presence of HIV-1-binding antibodies and for neutralizing activity. Along with these immunizations, the applicants will perform immunizations using peptides whose mimicked epitopes are structurally well characterized. This will allow the applicants to assess their immunization strategy on a structural level. The applicants will also assess the peptides for their ability to predict whether an HIV-1-infected person has made antibodies that are similar to the neutralizing monoclonal antibodies. From this, the applicants will determine whether similar neutralizing antibodies are made by different people.
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