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.

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。女性也有 比男性更强大的HIV特异性免疫反应，但男性表现出更多的外周T细胞活化， 增殖出乎意料的是，我们的初步数据显示，经历生殖老化的女性有一个 可诱导的细胞HIV RNA转录水平逐渐增加，而男性则表现出逐渐增加的 随着年龄的增长，艾滋病病毒的储存量会下降。然而，我们的初步数据缺乏直接关联的能力 随着雌激素水平的增加，储存库的扩大，我们还没有确定潜在的机制， 雌激素与艾滋病病毒持久性的关系鉴于感染艾滋病毒的老年妇女人数不断增加， 确定艾滋病毒持续存在和性激素下降的相互作用，以设计有效的艾滋病毒治疗策略。 我们的目标。对于目标1，我们将广泛描述HIV库的特征，并在 50名接受抗逆转录病毒治疗（ART）的中年HIV女性（未接受激素治疗）的每个时间点 受抑制的HIV RNA，已经被确定为妇女机构间HIV研究（WIHS）的一部分， MACS/WIHS联合队列研究（MWCCS）。我们将用这些数据来确定性激素的作用 对HIV储库大小，转录活性和炎症的影响超过10年的随访，而对ART。 目的2和3，我们将使用从绝经前和绝经后妇女前瞻性收集的细胞进行详细的 机制研究，并评估观察到的诱导型HIV储库的增加是否是由于 转录激活谱或HIV储库动力学的变化（IL-7驱动的稳态增殖和 抗原介导的增殖）。 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。特别是那些专为“踢死”而设计的特工 策略可能尤其受到雌二醇介导的机制的影响。更好地了解这些 这些差异将有助于设计未来可适用于两性的治疗方法。