Sex-differences in HIV persistence and Immune Dynamics during Reproductive Aging

生殖衰老过程中艾滋病毒持久性和免疫动态的性别差异

• 批准号: 10838316
• 负责人: Sara Gianella Weibel
• 金额: $ 83.95万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-22 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10838316
• 关键词: Affect; Aftercare; Age; Aging; Algorithms; Antibodies; Area; Automobile Driving; Bar Codes; Bioinformatics; Biological; Biological Assay; Biometry; Blood Cells; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Survival; Clinical; Clinical Data; Clonal Expansion; Cohort Studies; Collaborations; Cytokine Network Pathway; DNA; Data; Detection; Estradiol; Estrogen decline; Estrogens; Exclusion; Future; Gene Expression; Gene Expression Profile; Genes; Genetic Transcription; Goals; Gonadal Steroid Hormones; HIV; HIV Infections; HLA-DR Antigens; Hormones; IL7 gene; Immune; Immune response; Immunologics; Immunology; Immunophenotyping; Infection; Inflammation; Inflammatory; Inflammatory Response; Inflammatory Response Pathway; Interferon Type II; Knowledge; Measures; Mediating; Natural History; Natural Killer Cells; Outcome; Participant; Pathogenesis; Pathway interactions; Perimenopause; Peripheral; Pilot Projects; Plasma; Postmenopause; Premenopause; Process; Productivity; Proliferating; Protocols documentation; RNA; Race; Recording of previous events; Repression; Research; Role; Sampling; Series; Sex Differences; Signal Transduction; Site; Specimen; Standardization; Statistical Data Interpretation; T-Cell Activation; Testing; The Multicenter AIDS Cohort Study; Therapeutic; Time; Transcript; Transcriptional Regulation; Viremia; Woman; Women' s Interagency HIV Study; Work; antiretroviral therapy; biobank; cis-female; cis-male; cohort; cytokine; design; experience; experimental study; human subject; immune activation; immunological intervention; improved; inclusion criteria; inflammatory marker; insight; integration site; longitudinal design; male; men; middle age; monocyte; multimodal data; novel; reproductive; reproductive senescence; response; sex; single cell sequencing; single-cell RNA sequencing; time interval; transcriptomics; virology

ABSTRACT Background. Sex-based differences, largely controlled by sex hormones, affect the natural and treated history of HIV infection and HIV-specific immune responses. Our previous work has shown that estrogen potently represses HIV transcription, thus decreasing cellular HIV RNA in women compared to men. Unexpectedly, women undergoing reproductive aging have a progressive increase in levels of inducible HIV reservoir, while estrogen declines. This observed expansion of the reservoir as women age is in sharp contrast to the steady decline in the reservoir size observed in men. Given the increasing number of women aging with HIV, it is critical to determine the interplay of HIV persistence and declining sex hormones during reproductive aging to design effective HIV cure strategies. Our goal. Our study is specifically designed with samples from both cisgender men and women across the reproductive aging spectrum. We will first define the impact of reproductive aging on multiple features of the reservoir including size, transcriptional activity, along with a novel exploration of clonal expansion (Aim 1). Next, we will precisely define the immunologic changes over the course of reproductive aging, using single cell sequencing combined with immunophenotyping using DNA-barcoded antibodies (Aim 2). The data will be integrated, and key features established using advanced statistical analyses. Study Cohort: Longitudinal samples (viable cells, plasma), collected, processed, and stored using standardized protocols in the multi-site Women's Interagency HIV Study (WIHS) and Multicenter AIDS Cohort Study (MACS) cohorts will be utilized for all proposed experiments. First, we will carefully select 25 cisgender WWH on suppressive combination antiretroviral therapy (ART) with biologic samples representing four reproductive stages (reproductive/pre-menopause, menopausal transition/early and late perimenopause, post-menopause). Then, we will identify 25 MWH as controls using a multivariate propensity score based matching algorithm. After matching, stored samples collected between 2009 and 2019 will be selected based on similar time-intervals across both groups. How will we advance the field? To date, the majority of HIV cure research has used male participants and therefore a significant knowledge gap exists between men and women. We do not know if the same immune- modulatory interventions will be effective in promoting HIV RNA transcription in men and women and how declining sex hormones will impact their efficacy. Agents that are designed for “kick and kill” strategies may be impacted by estradiol-mediated mechanisms as women undergo reproductive aging. A better understanding of these differences will assist in the design of future cure approaches that can be applied across sexes.

摘要 背景基于性别的差异，主要由性激素控制，影响自然和治疗史 艾滋病毒感染和艾滋病毒特异性免疫反应。我们之前的研究表明雌激素 抑制HIV转录，因此与男性相比，女性细胞中的HIV RNA减少。没想到， 经历生育年龄的妇女的可诱导HIV储库水平逐渐增加， 雌激素下降。随着女性年龄的增长，观察到的水库扩大与女性的稳定形成鲜明对比。 在男性中观察到的储库大小下降。鉴于越来越多的妇女感染艾滋病毒， 为了确定艾滋病毒持续存在和生殖老化期间性激素下降的相互作用， 有效的艾滋病毒治疗策略。 我们的目标。我们的研究是专门设计的，样本来自全世界的顺性别男性和女性。 生殖老化谱我们将首先定义生殖老化对多个特征的影响， 水库，包括大小，转录活性，沿着与克隆扩张的新探索（目的1）。接下来， 我们将利用单细胞免疫学技术， 测序结合使用DNA条形码抗体的免疫表型分析（Aim 2）。数据将 集成，并使用先进的统计分析建立的关键功能。 研究队列：纵向样本（活细胞、血浆），使用标准化的 多中心妇女机构间艾滋病研究（WIHS）和多中心艾滋病队列研究（MACS） 所有提议的实验都将使用群组。首先，我们将精心挑选25个顺性别WWH上 抑制性联合抗逆转录病毒治疗（ART）与生物样本代表四个生殖 阶段（生殖/绝经前，绝经过渡/早期和晚期围绝经期，绝经后）。 然后，我们将使用基于多变量倾向评分的匹配算法确定25 MWH作为对照。后 将根据类似的时间间隔选择2009年至2019年期间收集的匹配存储样本 在两组中。 我们将如何推进这一领域？迄今为止，大多数艾滋病毒治疗研究都使用男性参与者， 因此，男女之间存在着巨大的知识差距。我们不知道是否同样的免疫- 调节干预将有效地促进男性和女性的HIV RNA转录，以及如何 性激素的下降会影响它们的功效。被设计用于“踢和杀”策略的代理可能是 受雌二醇介导机制的影响，因为女性经历生殖衰老。更好地了解 这些差异将有助于设计未来可适用于不同性别的治疗方法。