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

摘要 背景资料。基于性别的差异，主要受性激素控制，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之间的关系。我们之前的工作表明雌激素具有很强的药效 抑制HIV转录，因此与男性相比，女性细胞中的HIV RNA减少。出乎意料的是， 正在经历生殖老龄化的妇女的可诱导艾滋病毒蓄积物水平逐渐增加，而 雌激素水平下降。这种观察到的随着女性年龄增长而扩大的蓄水池与稳定的情况形成了鲜明对比 在男性中观察到的储存池大小的下降。鉴于越来越多的妇女感染艾滋病毒，这一点至关重要。 确定HIV持续存在与生殖衰老过程中性激素下降的相互作用 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，样本来自世界各地的顺性男女 生殖衰老谱系。我们将首先定义生殖老龄化对老年人多个特征的影响 储存库包括大小、转录活性，以及克隆扩张的新探索(目标1)。下一首, 我们将使用单细胞精确定义生殖衰老过程中的免疫学变化。 测序结合使用DNA条形码抗体的免疫表型(目标2)。数据将是 使用先进的统计分析确定的综合和关键特征。 研究队列：纵向样本(活细胞、血浆)，使用标准化方法收集、处理和存储 多站点妇女机构间艾滋病毒研究(WIHS)和多中心艾滋病队列研究(MACS)中的方案 所有拟议的实验都将利用队列。首先，我们将仔细挑选25个顺性别WWH在 代表四种生殖器的生物样本联合抗逆转录病毒疗法(ART) 各阶段(生殖/绝经前、绝经过渡/围绝经期早期和晚期、绝经后)。 然后，我们将使用基于多变量倾向分数的匹配算法确定25个MWH作为对照。之后 将根据相似的时间间隔选择2009至2019年间收集的匹配存储样本 在这两组人中。 我们将如何推进这一领域？到目前为止，大多数艾滋病毒治疗研究都使用了男性参与者和 因此，男性和女性之间存在着巨大的知识差距。我们不知道是否有同样的免疫力- 调节性干预将有效地促进男性和女性的艾滋病毒RNA转录以及如何 性激素的下降会影响它们的疗效。专为“先踢后杀”策略设计的特工可能 在妇女经历生殖老化时，受雌二醇介导的机制的影响。更好地理解 这些差异将有助于设计未来可应用于不同性别的治疗方法。

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.