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.

抽象的。 有问题。有明显的性别差异，影响艾滋病毒感染的自然历史和艾滋病毒- 特定的免疫反应。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储存库的大小、分布和转录活性。在全球范围内，女性 占所有艾滋病毒携带者的一半以上，但只占艾滋病毒治愈研究参与者的11% 导致男性和女性对艾滋病毒生物学的认识存在很大差距。我们所知的更少 当女性进入更年期，荷尔蒙水平开始下降时，这种影响会发生怎样的变化。 我们现在所知道的。 ·女性外周血单个核细胞(PBMC)中艾滋病毒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目标细胞复制的差异。 ·女性的艾滋病毒特异性免疫反应与男性不同。 ·这些差异部分是由雌二醇通过雌激素抑制外周血单核细胞中的艾滋病毒复制所致 受体依赖机制。最近的一项体外研究(由Jon Karn等人进行)提供了强有力的证据 雌激素以性别特异性的方式抑制艾滋病毒的转录活动。 建议的解决方案。我们将要求30名年龄在40-55岁的艾滋病毒感染妇女的纵向存储样本 登记(不接受激素治疗)和30名年龄相仿的男性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提高激素水平的可变性 (跨研究参与者和纵向)，因为年轻女性更有可能服用荷尔蒙 心理治疗。 我们的目标。我们将广泛分析艾滋病毒宿主的特征，并在每一时刻产生免疫学数据- 指向。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 在接受抗逆转录病毒治疗的3年以上的随访中，对艾滋病毒储存库的大小和转录活性的影响。我们会 将这些数据与一组相似的男性进行比较。 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。