Modeling Inflammation in HIV Transmission

HIV 传播中的炎症建模

基本信息

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
项目类别：
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

项目摘要

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 HIV 传播效率低下并且有预防 HIV 传播的方法，但仍有 260 万人感染了 HIV 每年。尽管 CAPRISA III 期试验发现替诺福韦杀菌剂可减少女性的 HIV 感染，但同一杀菌剂凝胶的后续 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来预防艾滋病毒感染，需要更详细地了解最有感染风险的艾滋病毒传播人群的生物学。生殖器炎症的存在与否至关重要，因为流行病学研究表明，患有由性传播感染（尤其是 HSV-2）引起的宫颈阴道炎症的女性感染 HIV-1 的风险会增加。然而，尽管存在流行病学关联并有间接证据支持，但仍不可能直接确定生殖器疾病的影响。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阴道暴露后 HIV 传播和传播中的作用。我们已经确定了阴道 SIVmac251 暴露后的靶细胞和传播途径以及创始人 SIV 变体的数量和性质。然而，所有这些研究都是在选择成熟猕猴的情况下进行的，没有考虑预先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的关键参数，进而改变疫苗或杀菌剂预防艾滋病毒传播的能力。这些参数包括感染个体所需的艾滋病毒剂量以及艾滋病毒从生殖道传播到全身组织的速率。一旦生殖器炎症情况下阴道 SIV 传播的病毒学特征得到确定，那么该 NHP 模型将可用于测试旨在预防 HIV 传播的候选疫苗和杀菌剂。此外，在本提案中，我们将提出并测试这样的假设：抗菌疗法和局部抗炎药相结合将减少生殖器炎症对传播的影响。