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: 10327456
• 负责人: Theresa L Chang
• 金额: $ 77.76万
• 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 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10327456
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Acute; Animal Model; Antiviral Agents; 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; 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 胃肠道故障和免疫激活仍然是重要的健康问题 抗逆转录病毒疗法时代的艾滋病毒/艾滋病（ART）。免疫激活燃料艾滋病毒储量已建立 感染和支持病毒在艺术中断（ATI）后反弹的早期。增加证据指向 HIV发病机理，疾病进展和持久性的性别差异。识别特定性别的免疫 与病毒持久性和反弹相关的参数对于我们发展的长期目标至关重要 个性化的治疗策略，可靠地阻止与HIV相关的慢性疾病，并针对艾滋病毒储量。 在没有艺术的受试者中，女性的免疫激活水平高于男性，并且具有更高的风险 开发辅助工具。在ART上感染HIV感染受试者的免疫激活中的性别差异不太明确， 可能是由于混杂因素，包括性别（涉及社会/行为因素）的差异 治疗。最新的证据鉴定雌激素受体1是CD4+ T细胞中HIV潜伏期的关键调节剂 表明雌激素信号传导参与HIV持久性的基于性别的差异。但是，角色 HIV中雌激素在体内的持续性仍然未知，因为雌激素会引起I型IFN和其他促进 炎性细胞因子，导致免疫激活。该领域的研究缺乏可靠的动物 模型。在这方面，我们开发了一个恒河猴（RM）模型，该模型模仿了人类的关键特征 艾滋病毒感染为追求基于性别的差异研究提供了有希望的途径。使用的模型 R5 SHIV C109直肠挑战显示出类似于人类艾滋病的疾病结果。在这个 模型，快速疾病进展仅发生在女性中，并伴有不受控制的粘膜 免疫反应。迄今已测试的所有男性RMS均表现出正常（缓慢/慢性）的进展。我们假设这一点 免疫失调的动力学和驱动病毒复制，持久性和反弹的动力学幅度 基于性别的差异，并且雌激素可能部分导致免疫反应中的性别差异和 病毒持久性。我们将确定与HIV相关的性别特异性免疫细胞和分子决定因素 水库和纵向反弹。雌激素对免疫调节性别差异的贡献和 还将检查病毒持久性。拟议的工作很重要，因为它有望提供新的 对肠道免疫激活和病毒持久性之间的串扰的见解，这些持久性差异 在男性和女性RMS中受到监管，这对于制定个性化的治疗策略至关重要 可靠地停止与HIV相关的慢性疾病，并靶向HIV储藏。