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: 9568360
• 负责人: Sara Gianella Weibel
• 金额: $ 19.71万
• 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 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9568360
• 关键词: AIDS clinical trial group; Address; Affect; Age; Aging; Androgens; Biological Assay; 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; 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; Virus Activation; Woman; aged; antiretroviral therapy; base; birth control; cohort; design; digital; follow-up; hormone therapy; immunological intervention; 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.

摘要。 问题.有明显的基于性别的差异，影响艾滋病毒感染和艾滋病毒的自然历史- 特异性免疫反应。这些差异部分是由性激素（特别是雌激素）驱动的 并可能影响HIV宿主的大小、分布和转录活性。在全球范围内，女性 占所有艾滋病毒感染者的一半以上，但仅占艾滋病毒治疗研究参与者的11% 导致男女对艾滋病毒的生物学知识存在巨大差距。我们知道的就更少了 当女性进入更年期，荷尔蒙水平开始下降时，这种影响是如何变化的。 我们现在知道的。 女性外周血单核细胞（PBMC）中的HIV DNA水平低于男性。 各种体外研究报告了艾滋病毒感染和靶细胞复制的性别差异。 ·女性的HIV特异性免疫反应与男性不同。 ·这些差异部分是由雌二醇驱动的，雌二醇通过雌激素抑制PBMC中的HIV复制 受体依赖机制最近的一项离体研究（Jon Karn等人）提供了强有力的证据， 雌激素以性别特异性方式抑制HIV转录活性。 建议的解决方案。我们将要求从30名40-55岁的艾滋病毒感染妇女中纵向储存样本， 入组（未接受激素治疗）和30名男性（年龄相似）接受抗逆转录病毒治疗（ART）， 抑制HIV RNA>48周。选择这个年龄范围是为了最大限度地增加激素水平的变异性 （跨研究参与者和纵向）并且因为年轻女性更有可能服用激素 疗法 我们的目标。我们将广泛地描述艾滋病毒储存库，并在每个时间产生免疫学数据- 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）对HIV储库大小和转录活性的影响。 将这些数据与类似的男性群体进行比较。 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。