HIV gp120 has recently been identified as an immunoglobulin superantigen (SAg), binding most members of the large VH3 gene family (approximately 10 percent of total serum IgM) in non-HIV-infected individuals. The concept put forth in this application is that HIV has evolved this SAg to enhance the efficiency of infection during mucosal transmission. Preliminary studies have shown that the level of SAg- binding antibodies is a polymorphic host trait, and that individuals highly susceptible to HIV correspond to those with the high phenotype SAg-binding trait. This preliminary finding supports the prediction that the high antibody phenotype is a host susceptibility factor in HIV transmission. To test this idea, the investigators will determine whether these antibodies enhance in vitro infection via an Fc alpha receptor-dependent mechanism and the types of cells targeted by this mechanism. Levels of SAg-binding IgA in gateway mucosal sites will be measured in parallel and determinations of whether individuals highly susceptible to mucosal transmission are high expressors for these antibodies will be made. Family and genotype studies will also be done to determine whether genetic factors contribute to the high expressor phenotype. Paradoxically, a striking predominance of anti-SAg antibodies is also associated with long term survivors of HIV infection. To understand this correlation, the investigators felt that anti-gp120 antibodies might also promote viral uptake by cell types bearing Fc gamma and/or C3R. Since such cells are mostly non-T cells, this may serve to redirect virus away from T cells and hence reduce viral pathogenesis. Initial in vitro studies demonstrate such immune sequestration of gp120 by anti-SAg IgM. The final two aims serve to further characterize and validate this protective mechanism in two ways. First, studies are designed to determine whether immune sequestration by anti-SAg inhibits HIV infection in vitro, through identifying the receptors and cell types involved in immune sequestration of gp120 in PBMCs, and the role of this mechanism on HIV infection of T cells in vitro. Second, reagents already developed to manipulate anti-SAg activity will be used to test whether anti-SAg Ig inhibits HIV pathogenesis in SCID-hu mice. If these ideas are validated, then this project will have defined a novel and important immunogenetic host factor in HIV infection, and a new class of target for the design of vaccines and other protective therapies.
