HIV-1 reservoir dynamics in the female genital tract

女性生殖道中 HIV-1 储存库动态

• 批准号: 8732343
• 负责人: ATHE M. TSIBRIS
• 金额: $ 91.85万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8732343
• 关键词: Anti-Retroviral Agents; Apoptosis; Area; BCL2 gene; Blood; Caring; Cells; Cervix Uteri; Comparative Study; Country; DNA; Endometrium; Entropy; Epidemic; Evolution; Female; Gagging; Genetic Transcription; Genital system; Genome; Goals; HIV; HIV Infections; HIV-1; Heterosexuals; Histone Deacetylase; Histone Deacetylase Inhibitor; Interdisciplinary Study; Interphase Cell; Investigation; Latent Virus; Length; Lymph Node Tissue; Maintenance; Measures; Mediating; Messenger RNA; Mitochondria; Nuclear; Participant; Patients; Penetration; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phenotype; Phylogenetic Analysis; Plasma; Plasma Cells; Population; Production; Protease Inhibitor; RNA; Relative (related person); Residual state; Resources; Risk; Sampling; Site; Source; T-Lymphocyte; Therapeutic; Tissues; Trees; Uterus; Vagina; Virus; Virus Replication; Woman; Women' s Group; Work; antiretroviral therapy; base; experience; gastrointestinal; improved; inhibitor/antagonist; insight; non-nucleoside reverse transcriptase inhibitors; novel; novel virus; peripheral blood; prevent; public health relevance; tool; transmission process

DESCRIPTION (provided by applicant): Effective combination antiretroviral therapy (ART) has transformed the HIV epidemic in resource-rich countries. Latently infected cells, referred to as the HIV reservoir, are rare but persist in treated patients and represent a major barrier to virus eradication. This reservoir is comprised of residual virus in plasma and latently infected peripheral blood mononuclear cell (PBMC) subpopulations that distribute into tissue compartments. The exact relationship between blood and tissue HIV reservoirs is not currently known. Much work is being done to characterize HIV reservoirs in gut and more recently lymph node tissues, whereas less is known about reservoirs in the genital tract. An improved understanding of HIV reservoir dynamics in tissue is critical to HIV eradication and cure efforts. The goal of this proposal is to help answer a fundamental question: Do measures of HIV persistence in the female genital tract provide novel insights into testable virus eradication strategies, relative to similar analyses performed in plasma and PBMC? The female genital tract has several unique features as an HIV reservoir that warrant further detailed study. First, while the presence of ongoing virus replication in blood or gastrointestinal tissues during suppressive ART remains controversial, the evidence for virus production in the female genital tract when plasma HIV-1 RNA levels are undetectable is well documented. Second, the antiretroviral drug tissue penetration of non-nucleoside reverse transcriptase inhibitors (NNRTIs) and some protease inhibitors (PIs) into female genital tract can be substantially reduced, relative to levels in plasma or PBMC, and may create conditions favorable for local maintenance and/or replenishment of the HIV reservoir during peripherally suppressive ART. We propose an interdisciplinary study to characterize the HIV reservoir in female genital tract, identify cellula and tissue sources of HIV persistence, investigate non-T cell reservoirs, define the impact of tissue drug levels on virus evolution, and establish the relationship between blood and female genital tract reservoirs. We hypothesize that the female genital tract HIV-1 reservoir is distinct n its decay and persistence during ART, compared to that in peripheral blood. We will investigate the contribution of antiretroviral drug tissue penetration to ongoing virus evolution and latency during suppressive ART, and explore the effects of virus reactivation strategies in tissue-derived cells. Specific aims of this proposal are: 1) Define the relationship between the peripheral blood and female genital tract HIV-1 reservoirs using two groups of women: treatment- naive participants initiating antiretroviral therapy and virologically suppressed subjects on stable ART, 2) Investigate female genital tract HIV-1 evolution during suppressive ART and correlate with tissue drug concentrations, and 3) Determine the sensitivity of female genital tract tissue reservoirs to virus re-activation strategies.

描述（由申请人提供）：有效的抗逆转录病毒疗法（ART）已改变了资源丰富的国家的艾滋病毒流行。被视为HIV储库的潜在感染细胞很少见，但在治疗的患者中持续存在，代表了消除病毒的主要障碍。该储层由血浆中的残留病毒和潜在感染的外周血单核细胞（PBMC）亚群，分布到组织室中。目前尚不清楚血液和组织HIV储藏之间的确切关系。为表征肠道中的艾滋病毒储量和最近的淋巴结组织正在做很多工作，而对生殖道中的储层知之甚少。对组织中HIV储层动力学的了解对消除HIV和治愈努力至关重要。该提案的目的是帮助回答一个基本问题：相对于在等离子体和PBMC中进行的类似分析，女性生殖道中的艾滋病毒持久性措施是否提供了对可检测病毒剥离策略的新见解？ 女性生殖道作为HIV储层具有多个独特的特征，需要进一步详细的研究。首先，虽然在抑制性艺术期间，血液或胃肠道组织中持续的病毒复制仍然存在争议，但当血浆HIV-1 RNA水平无法检测到时，雌性生殖道的病毒产生的证据已得到充分记录。其次，非核苷逆转录酶抑制剂（NNRTIS）和某些蛋白酶抑制剂（PI）抗逆转录病毒组织的渗透可以大大降低血浆或PBMC中的水平，并可能在局部维持和补充perip peripserversermatife peripermation peripserversermations peripsermation peripserversrife peripserveriir中，可能会降低。 我们提出了一项跨学科研究，以表征女性生殖道中的HIV储量，鉴定HIV持久性的细胞菌和组织来源，研究非T细胞储层，确定组织药物水平对病毒进化的影响，并建立血液与女性生殖道储层之间的关系。我们假设女性生殖道HIV-1储层与外周血相比，其在艺术期间的衰减和持久性是明显的。我们将研究抗逆转录病毒组织对抑制性艺术期间持续的病毒进化和潜伏期的贡献，并探索病毒重新激活策略对组织衍生细胞的影响。该提议的具体目的是：1）定义外周血和女性生殖道HIV-1储层使用两组妇女之间的关系：治疗 - 幼稚的参与者开始抗逆转录病毒疗法，并在稳定的艺术中受到病毒的抑制， 2）研究女性生殖道HIV-1在抑制ART期间的演变，并与组织药物浓度相关，3）确定女性生殖道组织储层对病毒重新激活策略的敏感性。