HIV activation in alcohol-aided G. vaginalis virulence

描述（由申请人提供）：这项探索性研究申请的目的是开辟一种创新的方法，以了解酒精增强的共感染因子毒力因子在妇女艾滋病传播中的作用。该应用程序提出测试新的假设，即阴道加德纳菌是女性主要的机会性HIV共感染因子，其特征是酒精增强了其重要毒力因子（即唾液酸酶）的活性。已知唾液化程度对人类HIV和其他灵长类慢病毒的复制程度和感染性有负相关影响。唾液酸酶是一种酶，已被证明可以从高度唾液化的病毒粒子包膜gp120和可感染的靶宿主细胞CD4/趋化因子受体上去除唾液酸，并在此过程中显著增强它们的高亲和力相互作用、病毒结合、进入宿主细胞和病毒复制。唾液酸酶的活性会因酗酒而增加许多倍。这一假设的一个推论是，唾液酸酶抑制剂的预防可以降低同时感染阴道加德纳菌和艾滋病毒的酗酒妇女感染艾滋病的风险。探索性R21应用拟验证以下子假设：1)加德纳菌唾液酸酶可有效去除gp120和CD4中的唾液酸；2)酒精提高了HIV病毒外壳gp120和CD4+靶细胞（如T淋巴细胞、单核细胞和外周血单核细胞）上的CD4的去唾液化的速度和程度；3) gp120和CD4的去唾液化促进HIV在靶细胞中的进入和复制；4)唾液酸酯酶抑制剂阻止阴道加德纳菌唾液酸酯酶增强病毒的进入和复制。艾滋病过程中公认的主要机会性传染因子，即真菌性肺炎球菌、链球菌和拟杆菌；原生克氏锥虫和真菌卡氏肺囊虫均表达唾液酸酶作为主要毒力因子。目前的应用使得共同感染微生物唾液酸酶作为一种促进艾滋病的细菌毒力因子与加德纳菌唾液酸酶特异性与女性相关的创新联系。已知与阴道加德纳菌微生物共同感染的刺激作用可促进女性艾滋病的进展，但其机制有待阐明。这一探索性研究应用可能有助于促进对这一现象的理解。

DESCRIPTION (provided by applicant): 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.