RC1: Effects of Chronic Alcohol Abuse on HIV in the Genital Mucosal Environment

RC1：长期酗酒对生殖器粘膜环境中艾滋病毒的影响

• 批准号: 8982186
• 负责人: ANGELA M AMEDEE
• 金额: $ 12.03万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8982186
• 关键词: AIDS/HIV problem; Affect; Age; Alcohol abuse; Alcohols; Animals; Anti-Retroviral Agents; Antiviral Agents; Biopsy; Cells; Cervical; Chronic; Clinical; Comorbidity; Complex; Development; Disease; Disease Progression; Dose; Environment; Epithelial Cells; Estrogens; Female; Genital system; Genotype; Gonadal Hormones; HIV; HIV Infections; Health; Hormonal; Human; Immune; Immunologics; Infection; Inflammatory; Intervention; Lactobacillus; Life; Link; Liquid substance; Longevity; Macaca; Macaca mulatta; Measures; Menopause; Modeling; Mucous Membrane; Mutation; Patients; Phenotype; Population; Predisposition; Proteins; Protocols documentation; Research; Research Design; Risk; SIV; Sampling; Submucosa; Sucrose; Surface; Survival Rate; T-Lymphocyte; Testing; Time; Tissue Sample; Tissues; Translating; Vagina; Viral; Viral Load result; Viral reservoir; Virus; Virus Diseases; Virus Replication; Virus Shedding; Woman; Women' s Health; abstracting; adaptive immunity; age effect; alcohol use disorder; cohort; disease transmission; genital secretion; high risk; lymph nodes; microbial; microbiota; prevent; reproductive tract; sexual HIV transmission; transmission process; vaginal fluid; vaginal transmission

Abstract LSUHSC CARC RC1: Effects of Chronic Alcohol Abuse on HIV in the Genital Mucosal Environment Alcohol use disorders (AUD) are a significant health problem worldwide, especially among those at risk for or living with HIV. Women comprise 50% of the HIV-infected population worldwide; therefore, it is increasingly important to understand how co-morbidities, such as AUD, affect HIV acquisition and disease progression in women. As survival rates among women with HIV have increased dramatically due to anti-retroviral therapy (ART), the effects of aging, menopause, and hormonal loss on HIV disease are also highly relevant, yet understudied issues for women's health. The experimental control afforded by the SIV-infected rhesus macaque model provides an ideal setting to decipher the specific mechanisms by which chronic binge alcohol abuse (CBA) affects HIV acquisition and disease progression. Our previous studies identified key changes in the female reproductive tract (FRT) of macaques exposed to CBA, which are consistent with a more favorable environment for HIV transmission. These included an increased percentage of HIV/SIV T-cell targets in the vaginal submucosa, increased presence of inflammatory cells, and alterations to the microbiota. Our observations have led us to hypothesize that CBA: (1) Enhances the acquisition and early replication of HIV following vaginal exposure by changing the function and distribution of submucosal immune cells and reducing the innate defenses of the genital compartment; and (2) Increases viral replication in tissue reservoirs specifically in the genital tract, resulting in the persistence and shedding of HIV within the reproductive tract; and (3) Exacerbates viral replication and shedding in the genital compartment of gonadal hormone-deficient females. Using rhesus macaque females exposed to either CBA or isocaloric sucrose (SUC) and SIV, we will evaluate these hypotheses in three aims. (1) We will evaluate the effects of CBA on the FRT through assessments of innate defense molecules and analysis of mucosal cell phenotypes. Subsequently, females will be inoculated with SIV using a multiple low-dose vaginal exposure protocol, to determine if CBA directly increases susceptibility to vaginal infection in females. (2) We will evaluate viral reservoirs in FRT tissue and draining lymph nodes to compare SIV levels and track founder viral genotypes in CBA and SUC animals over the course of ART. Additionally, this aim will evaluate vaginal fluid samples obtained from a clinical cohort of HIV-infected ART-treated women to translate and validate the results obtained from rhesus macaques in humans with AUD. (3) We will evaluate the combined effects of CBA and surgically-induced menopause on SIV disease and viral replication in the FRT of chronically-infected, ovariectomized macaques exposed to CBA/SUC. The results from these studies will aid in deciphering key mechanisms involved in transmission and genital HIV shedding in a high-risk female population that abuses alcohol, and thus guide the development of targeted interventions that can prevent HIV transmission and disease progression in the context of AUD.

摘要LSUHSC CARC RC1：慢性酒精滥用对生殖器粘膜中HIV的影响 环境 饮酒障碍（AUD）是全球重大的健康问题，尤其是在有风险或 与艾滋病毒一起生活。妇女占全球HIV感染人群的50％；因此，它越来越 重要的是要了解诸如AUD之类的合并症如何影响HIV的获取和疾病进展 女性。由于抗逆转录病毒疗法，由于艾滋病毒妇女的存活率显着增加 （ART），衰老，更年期和荷尔蒙丧失对艾滋病毒疾病的影响也很重要，但是 研究妇女健康的问题。 SIV感染的恒河猴提供的实验控制 猕猴模型提供了破译慢性酒精的特定机制的理想设置 滥用（CBA）会影响艾滋病毒的获取和疾病进展。我们以前的研究确定了关键变化 暴露于CBA的猕猴的女性生殖道（FRT）与更有利的 艾滋病毒传播的环境。其中包括增加的HIV/SIV T细胞靶标的百分比 阴道粘膜粘膜，炎性细胞的存在增加以及对微生物群的改变。我们的 观察结果使我们假设CBA：（1）增强了HIV的获取和早期复制 通过更改粘膜免疫细胞的功能和分布并减少阴道暴露后的阴道暴露 生殖器室的先天防御； （2）增加组织储层中的病毒复制 特别是在生殖道中，导致生殖道内的艾滋病毒的持久性和脱落； （3）加剧性腺激素缺陷的生殖器室中的病毒复制和脱落 女性。使用暴露于CBA或等量合理的蔗糖（SUC）和SIV的恒河猴猕猴，我们将 以三个目标评估这些假设。 （1）我们将评估CBA对FRT的影响 先天防御分子的评估和粘膜细胞表型的分析。随后，女性 将使用多种低剂量阴道暴露方案接种SIV，以确定CBA是否直接 增加女性阴道感染的敏感性。 （2）我们将评估FRT组织中的病毒储存库 排出淋巴结以比较CBA中的SIV水平并跟踪创始人的病毒基因型，并在 艺术进程。此外，此目的将评估从临床队列中获得的阴道样品 受艾滋病毒感染的艺术治疗妇女翻译和验证从恒河猕猴中获得的结果 人类与aud。 （3）我们将评估CBA和手术诱导的更年期对 长期感染的卵巢猕猴暴露于长期感染的卵巢疾病中的SIV疾病和病毒复制 CBA/SUC。这些研究的结果将有助于解释有关传播和 滥用酒精的高危女性人口中的生殖器艾滋病毒脱落，从而指导 有针对性的干预措施可以防止在AUD中进行HIV传播和疾病进展。