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.

抽象的 背景。基于性别激素的基于性别的差异影响了自然和治疗的历史 HIV感染和HIV特异性免疫反应。我们以前的工作表明雌激素有潜在 抑制HIV转录，因此与男性相比，女性的细胞HIV RNA降低。不料， 接受生殖衰老的妇女在诱导型艾滋病毒水库水平逐渐增加，而 雌激素下降。随着女性年龄的增长与稳定形成对比 男性观察到的储层大小的下降。考虑到越来越多的艾滋病毒妇女衰老，这是至关重要的 确定艾滋病毒持久性的相互作用，并在生殖老化期间的性恐怖症下降 有效的艾滋病毒治愈策略。 我们的目标。我们的研究是专门设计的。 生殖老化谱。我们将首先定义生殖老化对多个特征的影响 储层包括大小，转录活性，以及​​对克隆扩张的新探索（AIM 1）。下一个， 我们将使用单个细胞精确地定义生殖老化过程中的免疫学变化 测序结合使用DNA-Barcoded抗体结合免疫表型（AIM 2）。数据将是 使用高级统计分析建立的集成和关键功能。 研究队列：使用标准化的纵向样品（可行细胞，等离子体）收集，处理和存储 多站点妇女跨机构艾滋病毒研究（WIHS）和多中心艾滋病队列研究（MAC）中的方案 同类将用于所有提出的实验。首先，我们将仔细选择25个cisgender wwh 抑制性组合抗逆转录病毒疗法（ART）与代表四个复制性的生物样品 阶段（生殖/培育前，更年期过渡/早期和晚期，绝经后）。 然后，我们将使用基于多变量的匹配算法识别25 MWH作为对照。后 匹配的，在2009年至2019年之间收集的存储样品将根据相似的时间间隔选择 两组之间。 我们将如何发展该领域？迄今为止，大多数HIV治疗研究都使用了男性参与者， 因此，男女之间存在着重要的知识差距。我们不知道是否具有相同的免疫力 - 调节性干预措施将有效促进男性和女性的HIV RNA转录以及如何 性恐怖量下降将影响其效率。设计用于“踢和杀死”策略的代理商可能是 受雌二醇介导的机制的影响，因为女性经历了生殖衰老。更好地理解 这些差异将有助于设计可以在性别中应用的未来治愈方法。