Modeling Inflammation in HIV Transmission

描述(申请人提供)：尽管艾滋病毒的传播效率低下，而且有预防艾滋病毒传播的方法，但仍有260万人感染了艾滋病毒 每年都有。尽管CAPRISA第三阶段试验发现替诺福韦杀微生物剂减少了妇女的艾滋病毒感染，但同一杀微生物剂凝胶的后续语音第三阶段试验未能证明任何保护作用。因此，为了制定始终如一的有效干预措施，防止艾滋病毒感染，必须更详细地了解感染风险最大的艾滋病毒传播人群的生物学特征。生殖器炎症的存在或不存在至关重要，因为流行病学研究表明，由性传播感染，特别是HSV-2引起的宫颈阴道炎的妇女感染艾滋病毒-1的风险增加。然而，尽管有流行病学关联和支持的间接证据，但不可能直接确定生殖器的影响。 炎症对人类艾滋病毒传播的影响。该项目将使用非人类灵长类动物(NHP)模型来详细了解HSV2诱导的生殖器炎症在艾滋病毒传播和阴道暴露后传播中的作用。我们已经确定了阴道SIVmac251暴露后的靶细胞和传播途径，以及方正SIV变异体的数量和性质。然而，所有这些研究都是在选择成熟猕猴时进行的，而不考虑先前存在的生殖器炎症水平。炎症可能会影响艾滋病毒传播和发病机制中的关键参数，而这些参数反过来又会改变疫苗或杀微生物剂预防艾滋病毒传播的能力。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比率。一旦表征了生殖器炎症环境下SIV阴道传播的病毒学特征，这种NHP模型将用于测试旨在防止艾滋病毒传播的候选疫苗和杀微生物剂。此外，在这项建议中，我们将开发和测试假设，即结合抗菌治疗和局部抗炎药将减少生殖器炎症对传播的影响。

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.