HIV ACTIVATION IN ALCOHOL-AIDED G VAGINALIS VIRULENCE

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。这项研究旨在探索一种创新的方法，以了解酒精增强的联合感染剂毒力因子在促进女性艾滋病方面的作用。这项研究测试了一种新的假设，即阴道加德纳菌是女性主要的机会性艾滋病毒联合感染因子；阴道加德纳菌具有重要的毒力因子，即唾液酸酶。唾液酸酶是一种从高度唾液酸化的病毒被膜gp120和可感染的靶细胞CD4/趋化因子受体中去除唾液酸的酶，在这样做的过程中，显著增强了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。已知唾液酸化的程度会反过来影响艾滋病毒和其他灵长类慢病毒的复制程度和传染性。在狂饮期间，酒精水平会增强唾液酸酶的活性。这一假设的一个推论是，使用唾液酸酶抑制剂进行预防将降低合并感染阴道毛滴虫和艾滋病毒的酗酒妇女促进艾滋病的风险。经测试的以下子假设：1)加德纳菌唾液酸酶将有效地去除gp120和CD4中的唾液酸；2)酒精增加了HIV病毒外壳中gp120和CD4对T淋巴细胞、单核细胞和外周血单核细胞(PBMC)等CD4靶细胞上的gp120的这种去唾液酸的速率和程度；3)gp120和CD4的去唾液酸化促进了艾滋病毒在靶细胞中的进入和复制；以及4)唾液酸酶抑制剂阻止了阴道革兰氏菌对病毒进入和复制的增强。我们一直在测试各种唾液酸酶对HIV和SIV在细胞系和猕猴PBMC中的传染性的影响。总体而言，我们发现在感染前进行唾液酸酶治疗可以增加艾滋病毒和SIV在细胞中生长的能力。在酒精存在的情况下，这种影响会增强。

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.