The impact of HIV on accelerated aging in the female genital tract: a pilot trial of topical estradiol to improve the vaginal microbiome and symptoms of vaginal atrophy in menopausal women with HIV

HIV 对女性生殖道加速衰老的影响：局部雌二醇改善感染 HIV 的绝经期妇女阴道微生物组和阴道萎缩症状的试点试验

• 批准号: 9927356
• 负责人: Kerry Jeanne Murphy
• 金额: $ 19.76万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9927356
• 关键词: 16S ribosomal RNA sequencing; Acids; Age; Aging; Anaerobic Bacteria; Antibodies; Atrophic; Attention; Award; Bacteria; Bacterial Antigens; Bacterial Vaginosis; Biological Markers; Bone Diseases; Cardiovascular system; Cell Separation; Chronic; Clinical Trials; Conduct Clinical Trials; Cross-Sectional Studies; Data; Disease; Environment; Epithelial; Epithelium; Estradiol; Estrogens; Female; Flow Cytometry; Foundations; Funding; Future; Gastrointestinal tract structure; Genital system; HIV; HIV Infections; HIV Seronegativity; Health; Immune; Immunoglobulins; Incidence; Infection; Inflammation; Inflammatory Bowel Diseases; Laboratories; Lactobacillus; Life Expectancy; Link; Measures; Mediating; Menopause; Metagenomics; Metronidazole; Mucosal Immunity; Mucositis; Mucous Membrane; Neurocognitive; Persons; Phenotype; Physicians; Pilot Projects; Population; Postmenopause; Premature aging syndrome; Prevalence; Publishing; Randomized Clinical Trials; Risk; Sampling; Scientist; Severities; Swab; Symptoms; Techniques; Testing; Training; Translating; Urinary tract; Vagina; Woman; Women’s Interagency HIV Study; aged; antiretroviral therapy; base; career; clinical implementation; design; dysbiosis; healthspan; improved; men; microbiome; microbiome analysis; novel; pathogenic bacteria; pilot trial; prevent; randomized placebo controlled trial; reproductive tract; senescence; success; symptomatic improvement; transcriptome sequencing; translational study; treatment comparison; vaginal microbiome; vaginal mucosa; young woman

HIV is associated with accelerated and/or accentuated aging, which may be mediated by chronic inflammation, immune senescence, and/or long-term antiretroviral therapy. This translates to earlier incidence and increased prevalence of aging-related conditions including cardiovascular, neurocognitive and bone disease. Accelerated aging may also manifest as earlier and more significant changes in the female genital tract (FGT) mucosal environment, which may increase risk or severity of vaginal atrophy, urinary tract and other infections. However, the effects of HIV on FGT aging have received scant attention. Aging-associated changes in the FGT include dysbiosis of the vaginal microbiome (characterized by a predominance of diverse anaerobes and a decrease in acid-producing lactobacilli), increased inflammation, and disruption of epithelial integrity. Menopausal women living with HIV (WLWH) are more likely to develop symptoms at an earlier age than HIV- seronegative (HIV-) women. Further, our data suggests that dysbiosis occurs earlier in WLWH and is more pronounced in older compared to younger WLWH suggesting that dysbiosis may be impacted by both HIV infection and age. Although the precise mechanisms by which dysbiosis is linked to inflammation are unclear, coating of bacteria with antibodies may be a key factor. We will utilize a novel technique to measure the microbiome, IgSeq, which combines flow cytometry-based bacterial cell sorting and 16S rRNA sequencing to characterize immunoglobulin (Ig) coating of bacteria in the FGT with the hypothesis that Ig coating of bacteria may be protective and reduced in the setting of HIV and dysbiosis. To determine if HIV is associated with earlier and more significant age-associated changes in the FGT, we will conduct a cross-sectional study in 50 HIV+ and 50 HIV- menopausal women to compare changes in the vaginal microbiome and mucosal inflammation. We hypothesize that menopausal WLWH will develop genital tract aging earlier than HIV- menopausal women and that the magnitude of difference in aging biomarkers including increased dysbiosis, less bacterial Ig coating, and increased mucosal inflammation will be greater when comparing younger (45-55 years) and older (56-70 years) menopausal WLWH to younger and older HIV- menopausal women. Estrogen has been shown to improve atrophy symptoms and the vaginal microbiome in HIV- postmenopausal women but has not been studied in menopausal WLWH. We will therefore conduct a pilot randomized clinical trial in 50 HIV+ menopausal women with symptomatic vaginal atrophy to test the hypothesis that vaginal estradiol treatment will result in a more optimal Ig coated lactobacillus-dominant vaginal microbiome, reduction in mucosal inflammation, and improvement in symptoms. I will develop expertise in the conduct of clinical trials/studies in aging populations and cutting-edge laboratory techniques (IgSeq, RNAseq). I will also pursue training in analysis of microbiome data including metagenomics. This award will allow me to become an independently funded clinician scientist studying the impact of HIV on mucosal immunity and aging in the FGT.

HIV与加速和/或加重衰老有关，这可能是由慢性炎症介导的， 免疫衰老和/或长期抗逆转录病毒治疗。这意味着发病率更早， 与衰老有关的疾病的患病率，包括心血管、神经认知和骨骼疾病。加速 衰老也可能表现为女性生殖道（FGT）粘膜的更早和更显著的变化。 环境，这可能会增加阴道萎缩，尿路和其他感染的风险或严重程度。 然而，HIV对FGT衰老的影响很少受到关注。衰老相关的变化 FGT包括阴道微生物组的生态失调（特征在于多种厌氧菌占优势， 产酸乳酸杆菌减少）、炎症增加和上皮完整性破坏。 感染艾滋病毒的男性和女性（WLWH）更有可能在比艾滋病毒更早的年龄出现症状- 血清反应阴性（艾滋病毒阴性）妇女。此外，我们的数据表明，生态失调发生在WLWH更早， 与年轻的WLWH相比，老年人中的差异明显，这表明生态失调可能受到艾滋病毒 感染和年龄。尽管生态失调与炎症相关的确切机制尚不清楚， 用抗体包被细菌可能是一个关键因素。我们将利用一种新的技术来测量 微生物组，IgSeq，它结合了基于流式细胞术的细菌细胞分选和16 S rRNA测序， 表征FGT中细菌的免疫球蛋白（IG）涂层，假设细菌的IG涂层 可能是保护性的，并在艾滋病毒和生态失调的情况下减少。为了确定艾滋病毒是否与 FGT中与年龄相关的更早、更显着的变化，我们将在50年内进行一项横断面研究 HIV+和50名HIV-绝经期妇女比较阴道微生物组和粘膜的变化 炎症我们假设绝经期WLWH将比HIV更早发生生殖道老化- 绝经期妇女和衰老生物标志物的差异幅度，包括增加的生态失调， 当与年轻人（45-55岁）相比时，细菌IG涂层减少，粘膜炎症增加 年龄）和年龄较大（56-70岁）的绝经期WLWH到年轻和老年HIV-绝经期妇女。雌激素 已被证明可以改善艾滋病毒绝经后妇女的萎缩症状和阴道微生物组 但尚未在绝经期WLWH中进行研究。因此，我们将在50个国家进行一项试点随机临床试验， 有症状性阴道萎缩的HIV阳性绝经期妇女，以检验阴道雌二醇 治疗将导致更优化的IG包被的乳酸杆菌主导的阴道微生物组， 粘膜炎症和症状改善。我将发展专业知识，在进行临床 在老龄化人群和尖端实验室技术（IgSeq，RNAseq）的试验/研究。我也会追求 微生物组数据分析培训，包括宏基因组学。这个奖项将使我成为一个 独立资助的临床科学家研究HIV对FGT粘膜免疫和衰老的影响。