Viral and Host Factors Promoting Male-to-Female Transmission of HIV

促进艾滋病毒男性向女性传播的病毒和宿主因素

• 批准号: 8525318
• 负责人: Warner C. Greene
• 金额: $ 31.7万
• 依托单位: J. DAVID GLADSTONE INSTITUTES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8525318
• 关键词: Acquired Immunodeficiency Syndrome; Adult; Biological; Biological Assay; Biology of HIV Transmission; C Type Lectin Receptors; CCR5 gene; CD4 Positive T Lymphocytes; Cells; Cervical; Charge; Cleaved cell; Contraceptive Agents; Dendritic Cells; Development; Dextran Sulfate; Dose; Endometrial; Engineering; Enhancers; Environment; Epidemic; Failure; Female; Frequencies; Future; Generations; Genital system; HIV; HIV Infections; HIV-1; Heparin; Immature Monocyte; Infection; Inorganic Sulfates; Integration Host Factors; Investigation; Kinetics; Mediating; Menopause; Molecular; Monitor; Mucous Membrane; Nature; Nutrient; Peptide Hydrolases; Peptides; Play; Polymers; Process; Production; Progestins; Property; Proteins; Rest; Risk; Role; Seminal; Seminal Plasma; Seminal fluid; Site; Surface; T memory cell; Testing; Tissues; Unspecified or Sulfate Ion Sulfates; Vaccines; Viral; Viral Load result; Virion; Virus; Virus Diseases; Woman; base; cell type; cellular targeting; design; driving force; effusion; env Gene Products; env Genes; glycosylation; improved; in vitro Assay; inhibitor/antagonist; insight; macrophage; male; men; microbicide; neutralizing antibody; novel strategies; prevent; prophylactic; prostatic fraction Acid phosphatase isoenzyme; reproductive; research study; sperm cell; success; transcytosis; transmission process

Male-to-female (M-*F) transmission of HIV is a major force driving expansion of the global AIDS epidemic, Our overall objective is to assess the potentially important role played by select viral and host factors in HIV transmission biology. In Specific Aim 1, HIV transmission pairs will be used to test the hypothesis that the envelope proteins from viruses successfully transmitted to women differ from non-transmitted viruses by their fusogenic properties and/or target cell selectivity. Envelopes from transmitted viruses share common features including compact V1-V4 regions, decreased numbers of glycosylation sites, and a greater sensitivity to neutralizing antibodies. These viral envelopes may be imbued with special properties that favor virion fusion to target cells within the female reproductive mucosa. In Specific Aim 2, biological features of recently identified fibrillar peptides in semen that can enhance HIV infection 10-100,000-fold will be tested. These peptides, termed semen enhancer of HIV infection (SEVI), are produced by endoproteolytic cleavage of prostatic acid phosphatase, a highly abundant semen protein. They enhance HIV infection by sharply increasing virion attachment to target cells. Our studies will test the hypothesis that SEVI propels M->F transmission of HIV and further that SEVI antagonists may impair HIV infection of women. Our studies specifically seek to: 1) identify the cellular protease(s) responsible for the generation of SEVI, 2) test whether SEVI enhances virion transcytosis, frans-infection, and cell-cell infection, 3) explore whether SEVI production varies among males and whether HIV infection alters SEVI levels, and 4) investigate novel approaches for inhibiting the action of SEVI. Effective SEVI antagonists could find application in future multi-component microbicides designed to prevent HIV transmission to women. This project will also interact extensively with Projects 2 and 3 of this P01 application. Viruses containing primary transmitted envelopes will be provided for use in these projects. Fusion assays will be performed collaboratively to monitor effects of progestin contraceptives, menopause, and microbicides on HIV target cells within female reproductive mucosa. Semen, SEVI, and SEVI antagonists will also be profiled for potential "harm" effects on endometrial and cervical mucosa. Together, the multiple lines of investigation described in Project 1 promise to expand our understanding of the molecular basis for M-¿F transmission of HIV.

HIV 的男性向女性 (M-*F) 传播是推动全球艾滋病流行蔓延的主要力量。我们的总体目标是评估特定病毒和宿主因素在 HIV 传播生物学中所发挥的潜在重要作用。目标 1，HIV 传播对将用于检验以下假设：成功传播给女性的病毒的包膜蛋白与非传播病毒的融合特性和/或靶细胞选择性不同。传播病毒的包膜具有共同特征，包括紧凑的 V1。 -V4区域，糖基化位点数量减少，以及 这些病毒包膜可能具有特殊特性，有利于病毒颗粒与女性生殖粘膜内的目标细胞融合，最近在精液中发现的纤维状肽的生物学特征可以将 HIV 感染增强 10-100,000。这些肽被称为 HIV 感染精液增强剂 (SEVI)，是由内切蛋白水解产生的。 前列腺酸性磷酸酶（一种高度丰富的精液蛋白）的裂解通过急剧增加病毒粒子与靶细胞的附着来增强 HIV 感染。我们的研究将验证 SEVI 促进 HIV M->F 传播的假设，并进一步验证 SEVI 拮抗剂可能会损害 HIV 感染。我们的研究特别旨在：1) 确定导致 SEVI 产生的细胞蛋白酶，2) 测试 SEVI 是否增强病毒颗粒转胞吞作用，反式感染和细胞间感染，3) 探讨男性中 SEVI 的产生是否存在差异，以及 HIV 感染是否会改变 SEVI 水平，以及 4) 研究新的 有效的 SEVI 拮抗剂可以应用于未来旨在防止 HIV 传播给妇女的多成分杀微生物剂中。该项目还将与包含初级传播包膜的项目 2 和 3 广泛相互作用。将合作进行融合测定，以监测孕激素避孕药、绝经期和杀菌剂对女性生殖粘膜内 HIV 靶细胞的影响。还将分析精液、SEVI 和 SEVI 拮抗剂对子宫内膜和宫颈粘膜的潜在“危害”作用，项目 1 中描述的多线研究有望扩大我们对 M-¿ 分子基础的理解。 F 艾滋病毒的传播。