This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This research is to investigate an innovative approach towards understanding the role of alcohol-enhanced co-infective agent virulence factors in AIDS promotion in women. The research tests the novel hypothesis that Gardnerella vaginalis is a major opportunistic HIV co-infection agent for women; G. vaginalis features an important virulence factor, i.e, sialidase. Sialidase is an enzyme that removes sialic acid from highly sialylated virion envelope gp120 and infectable target host cell CD4/chemokine receptors and, in so doing, dramatically escalates their high affinity interaction, virus binding, entry into the host cell, and viral replication. The degree of sialylation is known to inversely affect the extent of replication and the infectivity of HIV and other primate lentiviruses. Sialidase activity is enhanced by alcohol levels that are achieved during binge drinking. A corollary of this hypothesis is that prophylaxis with sialidase inhibitors will reduce the risk of AIDS promotion in alcohol-abusing women co-infected with G. vaginalis and HIV. The following sub-hypotheses tested: 1) Gardnerella sialidase will effectively remove sialic acid from gp120 and CD4; 2) alcohol enhances the rate and extent of this de-sialylation of gp120 in the HIV viral coat and CD4 on CD4+ target cells such as T lymphoid, monocytoid, and peripheral blood mononuclear cells (PBMC); 3) the de-sialylation of gp120 and CD4 promotes HIV entry and replication in the target cell; and 4) that sialidase inhibitors prevent enhancement by G. vaginalis sialidase of viral entry and replication. We have been testing the effects of various sialidase enzymes on the infectivity of both HIV and SIV in cell lines and PBMC from macaques. In general we have found that sialidase treatment prior to infection increases the ability of HIV and SIV to grow in cells. This effect is increased in the presence of alcohol.
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