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

艾滋病毒与加速和/或加剧衰老有关，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。这转化为更早的发病率并增加了 与衰老有关的疾病，包括心血管疾病、神经认知疾病和骨骼疾病的流行。加速 衰老也可能表现为女性生殖道(FGT)粘膜更早和更显著的变化 环境，这可能增加阴道萎缩、尿路和其他感染的风险或严重程度。 然而，HIV对FGT衰老的影响还没有引起足够的重视。与年龄相关的变化 FGT包括阴道微生物群的失调(其特征是以各种厌氧菌和 产酸乳酸菌减少)，炎症增加，上皮完整性破坏。 更年期艾滋病毒携带者(WLWH)比艾滋病毒携带者更容易在更早的年龄出现症状。 血清阴性(HIV-)女性。此外，我们的数据表明，WLWH的生物失调发生得更早，而且更严重 与年轻的WLWH相比，年龄较大的WLWH患者明显，这表明生物失调可能受到两种艾滋病毒的影响 感染和年龄。尽管生物失调与炎症相关的确切机制尚不清楚， 用抗体包裹细菌可能是一个关键因素。我们将利用一种新技术来测量 Microbiome，IgSeq，它结合了基于流式细胞术的细菌细胞分类和16S rRNA测序 FGT中细菌免疫球蛋白(Ig)包被的特征 在艾滋病毒和生物失调的背景下，可能具有保护性和减少性。以确定艾滋病毒是否与 更早和更显著的FGT年龄相关变化，我们将在50%进行横断面研究 比较HIV和50例HIV绝经期妇女阴道微生物群和粘膜的变化 发炎。我们假设绝经期WLWH将比HIV更早地发展生殖道老化- 更年期妇女和衰老生物标记物的大小差异，包括加剧的生物失调， 细菌免疫球蛋白涂层较少，粘膜炎症增加，与年轻(45-55岁)相比更大 绝经期妇女(56-70岁)和年龄较大(56-70岁)的妇女中，艾滋病毒感染绝经期妇女的比例也有所下降。雌激素 已被证明可以改善HIV感染的绝经后妇女的萎缩症状和阴道微生物群 但尚未在更年期WLWH中进行研究。因此，我们将在50年内进行一项试点随机临床试验 HIV绝经期妇女有症状性阴道萎缩检验阴道雌二醇假说 治疗将导致更理想的Ig包被乳酸菌占优势的阴道微生物群，减少 粘膜发炎，症状改善。我将在临床指导方面培养专业知识 老龄化人口和尖端实验室技术的试验/研究(IgSeq，RNAseq)。我也会继续追查 微生物组数据分析方面的培训，包括元基因组学。这个奖项将让我成为一名 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。

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.