Impact of Reproductive Aging On HIV Persistence and Inflammation

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。女性也有 比男性更强健的HIV特异性免疫反应，但男性表现出更多的外周T细胞激活和 扩散。出乎意料的是，我们的初步数据显示，正在经历生殖年龄的女性 可诱导的细胞HIV RNA转录水平进行性增加，而男性表现出进行性 随着年龄的增长，艾滋病毒携带者的数量会减少。然而，我们的初步数据缺乏直接关联的能力 蓄水池的扩张与雌激素水平有关，我们还没有确定潜在的联系机制 雌激素对艾滋病毒的持久性。鉴于越来越多的妇女感染艾滋病毒，至关重要的是更准确地 确定艾滋病毒持久性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AIMS 1，我们将广泛描述艾滋病毒宿主的特征并生成免疫学数据，网址为 50名感染艾滋病毒的中年妇女(未接受激素治疗)的每个时间点接受抗逆转录病毒治疗(ART) 被抑制的艾滋病毒RNA，并已被确认为妇女机构间艾滋病毒研究(WIHS)的一部分 MACS/WIHS联合队列研究(MWCCS)。我们将使用这些数据来确定性激素的影响 在接受抗逆转录病毒治疗的同时，对艾滋病毒储存库的大小、转录活性和炎症进行了超过10年的随访。为 目标2和3，我们将使用预期收集的绝经前和绝经后妇女的细胞来进行详细的 机制研究，并评估观察到的可诱导艾滋病毒宿主的增加是否由于 转录激活谱或HIV储存库动态的变化(IL-7驱动的动态平衡增殖和 抗原介导的增殖)在生殖老化期间。 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。尤其是那些专为“踢杀”而设计的特工 策略可能尤其受到雌二醇介导性机制的影响。更好地理解这些 差异将有助于设计未来可以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. 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.