Modeling Inflammation in HIV Transmission

HIV 传播中的炎症建模

• 批准号: 8470022
• 负责人: CHRISTOPHER James MILLER
• 金额: $ 98.41万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8470022
• 关键词: Affect; Animals; Anti-Inflammatory Agents; Anti-Retroviral Agents; Anti-inflammatory; Biology; Biology of HIV Transmission; Biopsy; Blood; Cells; Clinical Trials; Conduct Clinical Trials; Conflict (Psychology); DNA; Dose; Epidemiologic Studies; Epidemiology; Gel; Genital system; HIV; HIV Infections; HIV vaccine; HIV-1; Heterosexuals; Human; Human Herpesvirus 2; Immune response; Immunofluorescence Immunologic; Immunohistochemistry; Immunology; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Irrigation; Macaca; Macaca mulatta; Messenger RNA; Methods; Modeling; Mucous Membrane; Nature; Pathogenesis; Pathway interactions; Pattern; Pharmaceutical Preparations; Phase III Clinical Trials; Population; Predisposition; Process; Prophylactic treatment; Proteins; Reverse Transcriptase Polymerase Chain Reaction; Risk; Role; SIV; Sampling; Scheme; Sexual Transmission; Sexually Transmitted Diseases; Swab; T-Lymphocyte; Technology; Tenofovir; Testing; Time; Tissues; Topical application; Vaccines; Vagina; Variant; Virus; Woman; antimicrobial; cervicovaginal; chemokine; cytokine; design; effective intervention; follow-up; men who have sex with men; microbicide; nonhuman primate; novel strategies; preclinical study; prevent; prophylactic; public health relevance; success; therapeutic vaccine; transmission process; truvada; vaccine candidate; virology

DESCRIPTION (provided by applicant): Despite the inefficiency of HIV transmission and the availability of methods to prevent HIV transmission, 2.6 million individuals acquire HIV infections every year. Although the CAPRISA Phase III trial found that tenofovir microbicide decreased HIV infection in women, the follow-up VOICE Phase III trial of the same microbicide gel failed to demonstrate any protection. Thus, in order to develop consistently effective interventions that can prevent HIV acquisition a more detailed understanding of the biology of HIV transmission populations most at risk for infection. The presence or absence of genital inflammation is of fundamental importance since and epidemiologic studies suggest that the risk of acquiring HIV-1 infection is increased in women with cervicovaginal inflammation induced by sexually transmitted infections especially HSV-2. However, despite the epidemiologic associations and supporting circumstantial evidence, it is not possible to directly determine the effects of genital inflammation on HIV transmission in humans. This project will use a non-human primate (NHP) model to provide a detailed understanding of the role of HSV2 induced genital inflammation in HIV transmission and dissemination after vaginal exposure. We have defined the target cells and dissemination pathways and the number and nature of founder SIV variants after vaginal SIVmac251 exposure. However, all these studies have been conducted with mature macaques chosen without regard to levels of pre-existing genital inflammation. Inflammation may affect critical parameters in HIV transmission and pathogenesis that, in turn can alter the ability of a vaccine or microbicide to prevent HIV transmission. These parameters include the dose of HIV required to infect an individual and the rate of HIV dissemination from the genital tract to systemic tissues. Once the virology of vaginal SIV transmission in the setting of genital inflammation is characterized, then this NHP model will be useful for testing candidate vaccines and microbicides designed to prevent HIV transmission. Moreover, in this proposal we will develop and test the hypothesis that combining antimicrobial therapy and topical anti-inflammatory agents will reduce the effect of genital inflammation on transmission.

描述（由申请人提供）：尽管艾滋病毒传播效率低下，而且预防艾滋病毒传播的方法可用，但仍有260万人感染艾滋病毒 每年尽管CAPRISA III期试验发现替诺福韦杀微生物剂降低了女性的艾滋病毒感染，但同一杀微生物剂凝胶的后续VOICE III期试验未能证明任何保护作用。因此，为了制定一致有效的干预措施，可以防止艾滋病毒的收购更详细的了解艾滋病毒传播的生物学最危险的感染人群。生殖器炎症的存在或不存在是至关重要的，因为流行病学研究表明，获得HIV-1感染的风险增加的妇女与宫颈阴道炎症引起的性传播感染，特别是HSV-2。然而，尽管存在流行病学关联和支持间接证据，但不可能直接确定生殖器感染的影响 炎症对人类艾滋病毒传播的影响。该项目将使用非人灵长类动物（NHP）模型，以详细了解HSV 2诱导的生殖器炎症在阴道暴露后HIV传播和传播中的作用。我们已经确定了靶细胞和传播途径以及阴道SIVmac 251暴露后创始SIV变体的数量和性质。然而，所有这些研究都是在不考虑预先存在的生殖器炎症水平的情况下选择成熟猕猴进行的。炎症可能会影响HIV传播和发病机制的关键参数，从而改变疫苗或杀微生物剂预防HIV传播的能力。这些参数包括感染一个人所需的艾滋病毒剂量和艾滋病毒从生殖道传播到全身组织的速度。一旦在生殖器炎症的情况下阴道SIV传播的病毒学特征，那么这个NHP模型将用于测试旨在预防HIV传播的候选疫苗和杀微生物剂。此外，在这项提案中，我们将开发和测试的假设，结合抗菌治疗和局部抗炎剂将减少生殖器炎症的影响传播。