Sex difference in intestinal immune dysfunction, SHIV infection and reservoir

肠道免疫功能障碍、SHIV感染和储存者的性别差异

• 批准号: 10462764
• 负责人: Theresa L Chang
• 金额: $ 76.2万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10462764
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Acute; Animal Model; Area; Blood; CD4 Positive T Lymphocytes; Cells; Chronic; Chronic Disease; Disease Outcome; Disease Progression; ESR1 gene; Epithelial; Estrogens; Exhibits; Feedback; Female; Fluorescent in Situ Hybridization; Fostering; Gender; Gene Expression; Genes; Goals; Gut associated lymphoid tissue; HIV; HIV Infections; HIV-1; Health; Human; Immune; Immune System Diseases; Immune response; ImmunoPET; Infection; Inflammatory; Interferon-alpha; Interferons; Interruption; Intestines; Kinetics; Knowledge; Longitudinal Studies; Macaca mulatta; Maps; Modeling; Molecular; Mucosal Immune Responses; Pathogenesis; Pathway interactions; Patients; Peripheral; Persons; Production; Reporting; Research; Reverse Transcriptase Polymerase Chain Reaction; Role; SIV; Sex Differences; Signal Transduction; Site; Social Behavior; Spatial Distribution; T-Cell Depletion; Technology; Testing; Therapeutic Intervention; Time; Tissues; Viral; Viral Load result; Viral reservoir; Virus; Virus Diseases; Virus Replication; Woman; Work; acute infection; antiretroviral therapy; base; cell type; cytokine; gastrointestinal; high risk; immune activation; immunoregulation; in vivo; insight; longitudinal analysis; macrophage; male; men; personalized therapeutic; response; sex; simian human immunodeficiency virus; single molecule; social engagement; transcriptome; transcriptome sequencing; viral RNA; viral rebound

PROJECT SUMMARY Gastrointestinal malfunctions and immune activation remain significant health issues for people living with HIV/AIDS in the era of anti-retroviral therapy (ART). Immune activation fuels HIV reservoirs that are established early during infection and support virus rebound after ART interruption (ATI). Increasing evidence points toward sex differences in HIV pathogenesis, disease progression, and persistence. Identifying sex-specific immune parameters associated with viral persistence and rebound will be critical to our long term goal of developing personalized therapeutic strategies to reliably halt HIV-associated chronic diseases, and to target HIV reservoirs. In subjects without ART, women have higher levels of immune activation than men and have a higher risk of developing AIDS. Sex differences in immune activation in HIV-infected subjects on ART are less definitive, possibly due to confounding factors, including gender (involving social/behavior factors) differences in seeking treatment. Recent evidence identifying estrogen receptor 1 as a key regulator of HIV latency in CD4+ T cells suggests the involvement of estrogen signaling in sex-based differences in HIV persistence. However, the role of estrogen in HIV persistence in vivo remains unknown, as estrogen induces type I IFNs and other pro- inflammatory cytokines, resulting in immune activation. Research in this area has been lacking a reliable animal model. In that regard, we have developed a rhesus macaque (RM) model that mimics key features of human HIV infection providing promising avenues for pursuing sex-based difference studies. The model, which employs R5 SHIV C109 intrarectal challenge, displays a spectrum of disease outcomes similar to human AIDS. In this model, fast disease progression occurs in females only, and is accompanied by an uncontrolled robust mucosal immune response. All male RMs tested to date exhibit normal (slow/chronic) progression. We hypothesize that kinetics and magnitude of immune dysregulation that drive viral replication, persistence, and rebound exhibit sex-based differences and that estrogen may partially contribute to sex difference in immune responses and viral persistence. We will determine sex-specific immune cellular and molecular determinants relevant to HIV reservoirs and rebound longitudinally. The contribution of estrogen to sex differences in immune regulation and viral persistence will also be examined. The proposed work is significant because it promises to provide new insights into the cross-talk between intestinal immune activation and viral persistence that are differentially regulated in male and female RMs, which will be critical for developing personalized therapeutic strategies to reliably halt HIV-associated chronic disease, and to target HIV reservoirs.

项目摘要 胃肠道功能障碍和免疫激活仍然是严重的健康问题， 抗逆转录病毒疗法时代的艾滋病毒/艾滋病。免疫激活为建立的艾滋病毒库提供燃料 在感染的早期，并支持ART中断（ATI）后的病毒反弹。越来越多的证据表明 艾滋病发病机制、疾病进展和持续性的性别差异。识别性别特异性免疫 与病毒持续性和反弹相关的参数对于我们开发 个性化的治疗策略，以可靠地阻止艾滋病毒相关的慢性疾病，并针对艾滋病毒库。 在未接受ART的受试者中，女性的免疫激活水平高于男性， 发展艾滋病。接受抗逆转录病毒治疗的艾滋病毒感染者免疫激活的性别差异不太确定， 可能是由于混杂因素，包括性别（涉及社会/行为因素）在寻求 治疗最近的证据表明雌激素受体1是CD 4 + T细胞中HIV潜伏期的关键调节因子 表明雌激素信号参与了艾滋病毒持久性的性别差异。然而，作用 雌激素在体内HIV持久性中的作用尚不清楚，因为雌激素诱导I型干扰素和其他前 炎症细胞因子，导致免疫激活。这方面的研究一直缺乏可靠的动物 模型在这方面，我们已经开发了一个恒河猴（RM）模型，模仿人类的关键特征， 艾滋病毒感染为进行基于性别的差异研究提供了有希望的途径。该模型采用 R5 SHIV C109直肠内激发，显示出一系列与人类AIDS相似的疾病结局。在这 在模型中，快速疾病进展仅发生在女性中，并伴有不受控制的稳健粘膜病变。 免疫反应迄今为止检测的所有雄性RM均表现出正常（缓慢/慢性）进展。我们假设 驱动病毒复制、持续存在和反弹的免疫失调的动力学和幅度表现出 基于性别的差异，雌激素可能部分导致免疫反应的性别差异， 病毒持久性我们将确定与艾滋病毒相关的性别特异性免疫细胞和分子决定因素 水库和反弹纵向。雌激素对免疫调节中性别差异的作用， 病毒的持久性也将被检查。这项拟议中的工作意义重大，因为它承诺提供新的 深入了解肠道免疫激活和病毒持久性之间的相互作用， 在男性和女性RM中调节，这对于开发个性化治疗策略至关重要， 可靠地遏制艾滋病毒相关的慢性疾病，并针对艾滋病毒储存库。