Chemoprophylaxis and HIV Host Interactions

化学预防和 HIV 宿主相互作用

• 批准号: 8924717
• 负责人: Robert M. Grant
• 金额: $ 66.51万
• 依托单位: J. DAVID GLADSTONE INSTITUTES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8924717
• 关键词: Address; Adult; Affect; Aftercare; Anti-Retroviral Agents; Antiviral Agents; Attenuated; Blood; CD4 Positive T Lymphocytes; Centers for Disease Control and Prevention (U.S.); Chemoprophylaxis; Consent; Cryopreserved Cell; Data; Data Analyses; Databases; Detection; Disease remission; Dose; Drug Exposure; Enrollment; Exposure to; Foundations; Gene Expression; Gene Expression Profile; HIV; HIV Infections; HIV-1; Heterosexuals; Human; Immune; Immune response; Incubated; Individual; Infant; Infection; Integration Host Factors; Intrinsic factor; Learning; Mississippi; Mucous Membrane; Nucleic Acids; Oral; Participant; Pattern; Persons; Pharmaceutical Preparations; Phase; Phenotype; Placebo Control; Placebos; Plasma; Predisposition; Prophylactic treatment; RNA; Recommendation; Regimen; Reporting; Research; Research Personnel; Resources; Risk; Specimen; Tenofovir; Tenofovir disoproxil fumarate; Testing; United States Food and Drug Administration; Ursidae Family; Vagina; Vaginal Gel; Viral; Viral Load result; Woman; World Health Organization; antiretroviral therapy; arm; base; cohort; immune activation; men; men who have sex with men; open label; public health relevance; rectal; sample collection; seroconversion; transcriptome sequencing; trend; uptake; viral DNA; viral RNA

 DESCRIPTION (provided by applicant): Pre-exposure prophylaxis (PrEP) using oral embriticitabine/tenofovir disoproxil fumarate (FTC/TDF) decreases HIV acquisition among men who have sex with men and adult heterosexual men and women. Based in part on evidence generated by the iPrEx trial, led by this team of investigators, oral FTC/TDF PrEP has received approval by the US Food and Drug Administration, and the World Health Organization and the US Centers for Disease Control have issued recommendations for its use. The subsequent iPrEx Open Label Extension (OLE) ecis the first PrEP demonstration project to evaluate factors associated with uptake of PrEP, effective use of PrEP, and sexual practices during open label access. All phases of the pioneering iPrEx studies were completed in June 2014. The project proposed here will leverage the uniquely valuable collections of specimens and data from the recently completed iPrEx studies to answer key unanswered questions about how antiretroviral drug exposure in HIV exposed persons could attenuate the course of infection, and by what mechanisms. There are now precedents that early exposure to antiretroviral drugs can alter the course of infection (eg: the Visconti cohort) or cause prolonged viral remission (eg: the Mississippi infant). We found that seroconversion in the first 12 weeks of PrEP use, associated with detectable viral RNA detection prior to PrEP use, was less frequent in the active arm compared with placebo arm in two PrEP trials (iPrEx and CAPRISA 004). Trends toward this imbalance are evident in all PrEP trials, suggesting that nascent infection may be attenuated in some people who achieve high concentrations of antiretroviral drugs, as might occur in the rectal mucosa after oral FTC/TDF dosing or in the vaginal mucosa after use of a tenofovir vaginal gel. In aim 1, we will seek evidence of aborted HIV infection among more than 1000 iPrEx participants who started oral FTC/TDF and never seroconverted, even during gaps in PrEP use. The impact of PrEP medications, and viral exposure during PrEP use, on the host will be explored using an analysis of global host gene expression that optimally utilizes the uniquely valuable specimens from these trials. We will learn how exposure to PrEP drugs could diminish immune activation in a manner that contributes to PrEP's protective benefit. We will also learn whether diminished immune activation and expression of intrinsic anti-viral factors in the absence of PrEP are associated with subsequent susceptibility to HIV infection. These hypotheses will be evaluated in aim 2 using state-of-the-art global assessment of the human transcriptome at baseline prior to PrEP use, after HIV infection, and after antiretroviral exposure Taken together, this project will leverage the uniquely valuable iPrEx specimen bank and database to test specific hypotheses that bear directly on PrEP activity, HIV cure, persistent infection, host factors governing susceptibility to infection.