Impact of Reproductive Aging On HIV Persistence and Inflammation

生殖衰老对艾滋病毒持续性和炎症的影响

• 批准号: 10433074
• 负责人: Sara Gianella Weibel
• 金额: $ 84.26万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-12 至 2023-09-21
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10433074
• 关键词: Affect; Age; Aging; Antigens; Bioinformatics; Biological Assay; Biometry; CD4 Positive T Lymphocytes; Categories; Cells; Characteristics; Clonality; Cohort Studies; DNA; Data; Detection; Elongation Factor; Environment; Enzyme-Linked Immunosorbent Assay; Estradiol; Estrogens; Flow Cytometry; Funding; Future; Genes; Genetic Transcription; Goals; Gonadal Steroid Hormones; HIV; HIV Infections; Hormones; IL7 gene; Immune; Immune response; Immunologics; Immunology; Individual; Infection; Inflammation; Intervention; Knowledge; Link; Maintenance; Measures; Mediating; Menopause; National Institute of Allergy and Infectious Disease; Natural History; Participant; Pathogenesis; Peptide Initiation Factors; Peptides; Peripheral; Plasma; Postmenopause; Premenopause; Progesterone; RNA; Recording of previous events; Research; Role; Sampling; Scientist; Signal Transduction; Statistical Models; T cell clonality; T-Cell Activation; T-Lymphocyte; Testing; Time; Transcript; Transcription Initiation; Transcriptional Activation; Transcriptional Regulation; United States National Institutes of Health; Woman; Women' s Interagency HIV Study; Work; antiretroviral therapy; base; cohort; design; differential expression; exhaustion; follow-up; hormone therapy; immune activation; immune function; immunological intervention; integration site; jun Oncogene; male; men; middle age; monocyte; programs; prospective; reproductive; reproductive senescence; senescence; sex; single-cell RNA sequencing; transcription factor; transcriptomics; virology; young woman

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. Women also have more robust HIV-specific immune responses than men, but men show more peripheral T-cell activation and proliferation. Unexpectedly, our preliminary data has shown that women undergoing reproductive aging have a progressive increase in levels of inducible cellular HIV RNA transcription, whereas men show a progressive decline in the HIV reservoir as they age. However, our preliminary data lack the power to directly correlate expansion of the reservoir with estrogen levels and we have not identified the underlying mechanisms linking estrogen to HIV persistence. Given the increasing number of women aging with HIV, it is critical to more precisely determine the interplay of HIV persistence and declining sex hormones to design effective HIV cure strategies. Our goal. For aims 1, we will characterize extensively the HIV reservoir and generate immunological data at each time-point for 50 midlife women with HIV (none taking hormone therapy) on antiretroviral therapy (ART) with suppressed HIV RNA and already identified as part of Women's Interagency HIV Study (WIHS) and MACS/WIHS Combined Cohort Study (MWCCS). We will use these data to determine the effect of sex hormones on the HIV reservoir size, transcriptional activity and inflammation over 10 years of follow-up while on ART. For aim 2 and 3, we will use prospectively collected cells from pre- and post-menopausal women to perform detailed mechanistic studies and to evaluate whether the observed increase in the inducible HIV reservoirs is due to changes in transcriptional activation profiles or HIV reservoir dynamics (IL-7 driven homeostatic proliferation and antigen mediated proliferation) during reproductive aging. 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. In particular, agents that are designed for “kick and kill” strategies may be especially impacted by estradiol-mediated mechanisms. 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。女人也有 与男性相比，HIV特异性免疫反应更强大，但男性表现出更多的外围T细胞激活和 增殖。出乎意料的是，我们的初步数据表明，经历生殖衰老的女性具有 诱导型细胞HIV RNA转录水平的逐步增加，而男性则表现出渐进性 随着年龄的增长，艾滋病毒水库的下降。但是，我们的初步数据缺乏直接关联的能力 储层的扩展具有雌激素水平，我们尚未确定联系的基本机制 雌激素到艾滋病毒的持久性。鉴于越来越多的妇女艾滋病毒衰老，对于更精确的 确定艾滋病毒持久性的相互作用，并减少性恐怖，以设计有效的艾滋病毒治愈策略。 我们的目标。对于目标1，我们将广泛表征艾滋病毒储量，并在 50名艾滋病毒中年女性（无接受龙骑手疗法）的每个时间点（ART） 被抑制的HIV RNA，已经被确定为妇女间艾滋病毒研究（WIHS）的一部分和 MAC/WIHS组合队列研究（MWCCS）。我们将使用这些数据来确定性恐怖的效果 在ART期间，在10年的随访中，在HIV储层的大小，转录活性和炎症上。为了 AIM 2和3，我们将使用前和绝经后妇女的前瞻性收集细胞进行详细 机械研究并评估观察到的诱导HIV储层的增加是否是由于 转录激活轮廓或HIV储层动力学的变化（IL-7驱动的稳态增殖和 抗原介导的增殖）在生殖衰老过程中。 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 性骑士的下降将影响其有效性。特别是为“踢和杀死”而设计的特工 策略可能特别受雌二醇介导的机制影响。更好地理解这些 差异将有助于设计可以在男女之间应用的未来治愈方法。