The objective of this exploratory research application is to open an innovative approach towards understanding the role of alcohol-enhanced co-infective agent virulence factors in AIDS promotion in women. The application proposes to test the novel hypothesis that Gardnerella vaginalis is a major opportunistic HIV co-infection agent for women that features alcohol enhanced activity of its important virulence factor, i.e sialidase. The degree of sialylation is known to inversely affect the extent of replication and the infectivities of human HIV and other primate lentiviruses. Sialidase is an enzyme that has been shown to remove sialic acid from highly sialylated virion envelope gp120 and infectable target host cell CD4/chemokine receptors and, in so doing, dramatically escalate their high affinity interaction, virus binding, entry into the host cell, and viral replication. Sialidase activity is enhanced many-fold 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 Gardnerella vaginalis and HIV. The exploratory R21 application proposes to test the following sub-hypotheses: 1) that Gardnerella sialidase will effectively remove sialic acid from gp120 and CD4; 2) that 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; 3) that de-sialylation of gp120 and CD4 promotes HIV entry and replication in the target cell; 4) that sialidase inhibitors prevent enhancement by Gardnerella vaginalis sialidase of viral entry and replication. The major recognized opportunistic infectious agents in the course of AIDS, namely the Eubacteriales pneumococcus, streptococcus, and bacteriodes; the protist Trypanosoma cruzi, and the fungus pneumocystis carinii all express sialidase as a major virulence factor. The present application makes the innovative connection of co-infective microbial sialidase as an AIDS-promoting bacterial virulence factor and that of Gardnerella sialidase relatable specifically to women. The stimulatory effect of co-infection with the Gardnerella vaginalis microorganism is known to advance AIDS progression in women, but the mechanism needs to be elucidated. This exploratory research application may help advance understanding of this phenomenon.
