Effect of Declining Sex Hormones on HIV persistence in HIV Infected Women on ART

性激素下降对接受 ART 的 HIV 感染妇女中 HIV 持续存在的影响

• 批准号: 9482258
• 负责人: Sara Gianella Weibel
• 金额: $ 24.41万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-20 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9482258
• 关键词: AIDS clinical trial group; Address; Affect; Age; Aging; Androgens; Biology; Blood; Blood Tests; CD28 gene; CD3 Antigens; CD4 Positive T Lymphocytes; Cells; DNA; Data; Detection; Down-Regulation; Enrollment; Enzyme-Linked Immunosorbent Assay; Estradiol; Estrogen Receptors; Estrogens; Event; Flow Cytometry; Follicle Stimulating Hormone; Fulvestrant; Future; Genetic Transcription; Goals; Gonadal Steroid Hormones; HIV; HIV Infections; Hormonal; Hormone Receptor; Immune; Immune response; Immunologics; In Vitro; Intervention; Knowledge; Life; Luteinizing Hormone; Measures; Mediating; Menopause; Natural History; Participant; Pathogenesis; Peripheral; Peripheral Blood Mononuclear Cell; Plasma; Progesterone; Prolactin; RNA; Reporting; Research; Sampling; Sex Hormone-Binding Globulin; T cell response; T-Lymphocyte; Testosterone; Time; Transcript; Woman; aged; antiretroviral therapy; base; birth control; cohort; design; digital; follow-up; hormone therapy; killings; male; men; men' s group; mullerian-inhibiting hormone; receptor expression; sex; study population; young woman

ABSTRACT. Problem. There are distinct sex-based differences that affect the natural history of HIV infection and HIV- specific immune responses. These differences are partially driven by sex hormones (estrogens in particular) and might influence the size, distribution and transcriptional activity of the HIV reservoirs. Globally, women account for over half of all people living with HIV but represent only 11% of participants in HIV cure research resulting in a significant knowledge gap between the biology of HIV in men and women. Even less is known about how this effect changes when women are entering menopause and hormonal levels starts to decline. What we know now. • Women have lower levels of HIV DNA in peripheral blood mononuclear cells (PBMCs) than men. • Various in vitro studies reported sex-based differences on HIV infection and replication in target cells. • Women have different HIV-specific immune responses than men. • These differences are partially driven by estradiol that inhibits HIV replication in PBMCs through estrogen receptor dependent mechanisms. A recent ex vivo study (by Jon Karn et al) provided strong evidence that estrogen inhibits HIV transcriptional activity in a sex-specific manner. Proposed Solution. We will request longitudinal stored samples from 30 HIV-infected women aged 40-55 at enrollment (not taking hormonal therapy) and 30 men (similar age) on antiretroviral therapy (ART) with suppressed HIV RNA for >48 weeks. This age range was selected to maximize variability in hormonal levels (across study participants and longitudinally) and because younger women are more likely to take hormonal therapy. Our goal. We will characterize extensively the HIV reservoir and generate immunological data at each time- point. We will use these data to determine the effect of sex hormones and receptor expression (in particular estradiol) on the HIV reservoir size and transcriptional activity over 3+ years of follow-up while on ART. We will compare these data with a similar group of men. 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。 问题。存在明显的基于性别的差异，会影响艾滋病毒感染和艾滋病毒的自然病史 特定的免疫反应。这些差异部分由性激素驱动（尤其是雌激素） 并可能影响HIV储层的大小，分布和转录活性。在全球范围内，女性 占所有艾滋病毒的人的一半以上，但仅占艾滋病毒治疗研究的11％的参与者 导致男性和女性艾滋病毒生物学之间存在很大的知识差距。甚至更少知道 关于当女性进入更年期和荷尔蒙水平开始下降时，这种影响如何变化。 我们现在知道的。 •女性在外周血单核细胞（PBMC）中的HIV DNA水平低于男性。 •各种体外研究报告了基于性别的艾滋病毒感染和靶细胞复制的差异。 •妇女的HIV特异性免疫复杂与男性不同。 •这些差异部分由雌二醇驱动，雌二醇通过雌激素抑制PBMC中的HIV复制 接收器依赖机制。最近的一个离体研究（乔恩·卡恩等人）提供了有力的证据表明 雌激素以性别特异性抑制HIV转录活性。 建议的解决方案。我们将要求来自30名40-55岁的HIV感染妇女的纵向存储样本 参加抗逆转录病毒疗法（ART）的入学人数（不接受马疗法）和30名男性（类似年龄） 抑制HIV RNA> 48周。选择该年龄范围以最大化荷尔蒙水平的变异性 （跨研究参与者和纵向），因为年轻女性更有可能服用Horsemonal 治疗。 我们的目标。我们将广泛表征HIV储层，并在每个时间生成免疫数据 观点。我们将使用这些数据来确定性激素和受体表达的影响（特别是 雌二醇）在3年以上的ART期间进行3年以上的HIV储层大小和转录活性。我们将 将这些数据与类似的男性进行比较。 我们将如何发展领域。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。