HIV activation in alcohol-aided G. vaginalis virulence

酒精辅助的阴道加泰罗尼亚毒力中的 HIV 激活

• 批准号: 6941750
• 负责人: ABRAHAM ROSENBERG
• 金额: $ 15.3万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6941750
• 关键词: AIDS; HIV envelope protein gp120; HIV infections; Macaca; T lymphocyte; alcoholism /alcohol abuse; bacteria; bacteria infection mechanism; cell line; chemokine; clinical research; comorbidity; cytokine receptors; enzyme activity; enzyme linked immunosorbent assay; exo alpha sialidase; helper T lymphocyte; host organism interaction; human subject; macrophage; microorganism culture; monocyte; virulence; virus infection mechanism; virus replication

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.

描述（由申请人提供）：这项探索性研究申请的目的是打开一个创新的方法，了解酒精增强的共感染因子毒力因子在女性艾滋病促进中的作用。该申请提出测试新假设，即阴道加德纳菌是女性的主要机会性HIV合并感染因子，其特征在于酒精增强其重要毒力因子（即唾液酸酶）的活性。已知唾液酸化的程度对人类HIV和其他灵长类慢病毒的复制程度和感染性有相反的影响。唾液酸酶是一种已显示从高度唾液酸化的病毒体包膜gp 120和可感染的靶宿主细胞CD 4/趋化因子受体中去除唾液酸的酶，并且在这样做时，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。唾液酸酶活性增强许多倍的酒精水平，达到酗酒。这一假设的一个推论是，用唾液酸酶抑制剂预防将降低合并感染阴道加德纳菌和艾滋病毒的酗酒妇女的艾滋病传播风险。探索性R21应用提出测试以下子假设：1）加德纳菌唾液酸酶将有效地从gp 120和CD 4中去除唾液酸; 2）酒精增强HIV病毒外壳中的gp 120和CD 4+靶细胞如T淋巴细胞、单核细胞样细胞和外周血单核细胞上的CD 4的这种去唾液酸化的速率和程度; 3）gp 120和CD 4的去唾液酸化促进HIV进入靶细胞并在靶细胞中复制; 4）唾液酸酶抑制剂防止加德纳氏菌唾液酸酶增强病毒进入和复制。在艾滋病过程中，主要公认的机会性感染因子，即真杆菌目肺炎球菌、链球菌和拟杆菌;原生生物克氏锥虫和真菌卡氏肺孢子虫都表达唾液酸酶作为主要毒力因子。本申请使作为促进AIDS的细菌毒力因子的共感染微生物唾液酸酶与女性特异性相关的加德纳菌唾液酸酶的创新联系。已知与Gardnerella vagulosa微生物共感染的刺激作用可促进女性艾滋病进展，但其机制需要阐明。这种探索性的研究应用可能有助于促进对这一现象的理解。