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: 6698202
• 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/6698202
• 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开启一种创新的方法，以了解酒精增强的共同感染剂毒力因素在促进妇女艾滋病方面的作用。该应用程序建议测试这一新的假设，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，其特征是酒精增强了其重要毒力因子，即唾液酸酶的活性。已知唾液酸化的程度会相反地影响人类艾滋病毒和其他灵长类慢病毒的复制程度和传染性。唾液酸酶是一种酶，可以从高度唾液酸化的病毒被膜gp120和可感染的靶细胞CD4/趋化因子受体上去除唾液酸，从而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。在狂饮过程中，酒精水平会使唾液酸酶活性提高许多倍。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加德纳菌和艾滋病毒的酗酒妇女促进艾滋病的风险。R21的探索性应用建议检验下列子假设：1)加德纳氏菌唾液酸酶将有效地从gp120和CD4中去除唾液酸；2)酒精提高了HIV病毒外壳中gp120和CD4+靶细胞(如T淋巴样细胞、单核细胞和外周血单核细胞)上gp120和CD4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；4)唾液酸酶抑制剂阻止了阴道加德纳菌唾液酸酶对病毒进入和复制的增强。在艾滋病过程中公认的主要机会性感染源，即真细菌、肺炎球菌、链球菌和类细菌；原生锥虫和卡氏肺孢子虫都表达唾液酸酶作为主要毒力因子。本申请使共同感染的微生物唾液酸酶作为促进艾滋病的细菌毒力因子与加德纳氏菌唾液酸酶的创新联系特别与妇女相关。与阴道加德纳氏菌混合感染的刺激作用已知会促进女性艾滋病的进展，但其机制需要阐明。这种探索性的研究应用可能有助于加深对这一现象的理解。