Sex, Gender and the Immunopathogenesis of HIV

性、性别和艾滋病毒的免疫发病机制

• 批准号: 10433924
• 负责人: Eileen Patricia Scully
• 金额: $ 53.73万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-10 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10433924
• 关键词: Accounting; Address; Age; Anatomy; Automobile Driving; Behavioral; Biological; Birth; Brazil; CCR5 gene; CD4 Positive T Lymphocytes; Caring; Cause of Death; Characteristics; Clinical Data; Collaborations; Collection; Communities; Comparative Biology; Complex; Data; Data Set; Development; Disease; Disease Progression; Estrogens; Exposure to; Female; Gender; Gender Identity; Gene Dosage; Gene Expression Profile; Gene Expression Profiling; Genes; Genetic Determinism; Genomics; Gonadal Steroid Hormones; HIV; HIV Infections; Hormonal; Hormone use; Hormones; Immune; Immune response; In Vitro; Individual; Infection; Inflammation; International; Knowledge; Life Cycle Stages; Maintenance; Measures; Mental Depression; Minority; Outcome; Participant; Pathogenesis; Pathologic; Pathology; Pathway interactions; Pattern; Persons; Phenotype; Population; Prevalence; Research; Research Design; Research Personnel; Risk; Role; Sex Chromosomes; Sex Differences; Signal Transduction; T-Cell Activation; TLR7 gene; Testing; Time; Trauma; United States; Ursidae Family; Variant; Viral Load result; Viral reservoir; Virus; Woman; Work; advanced disease; autosome; base; biological sex; cis-female; cis-male; cohort; design; epidemiologic data; experience; experimental study; gender difference; gender-based violence; genetic architecture; genetic variant; genomic data; genomic variation; genotypic sex; girls; hormone therapy; immune activation; infection burden; insight; intimate partner violence; latent HIV reservoir; male; men; novel; novel therapeutic intervention; preventive intervention; sex; social; therapeutic target; transgender women; treatment trial

Project Summary Biological sex is associated with clear differences in HIV immunopathogenesis, but there is limited understanding of the mechanisms of this variation. There are 19.1 million women and girls living with HIV infection, accounting for slightly more than half of the people living with HIV globally, but women are generally a minority of study participants and sex-stratified analyses are uncommon. Transgender women bear a disproportionate burden of infection, and even fewer studies have sought to understand the biological impact of female gender identity on HIV infection outcomes. Studies of sex and gender differences in the mechanistic pathways driving immune responses to infection, pathologic inflammation and control of the HIV reservoir are critical to the development of novel therapeutic interventions. In this proposal, we investigate both biological sex and female gender identity to disentangle their contributions to immune pathology. Specifically, we will work with the extensive genomic and clinical data in the International Collaboration for the Genomics of HIV (ICGH) dataset to analyze genetic determinants of HIV disease progression on the sex chromosomes and in a sex stratified analysis of the autosomes. We will also work with the Transcendendo cohort in Brazil, a cohort designed with community input to follow individuals assigned a male sex at birth and living with a female gender. We will design groups for the collection of biospecimens from cohort participants selected based on differing use of gender-affirming hormone therapy, HIV infection status, and accounting for critical covariates including trauma and depression. With immune transcriptional profiling, we will assess the impact of gender identity on immune activation profiles, to inform the understanding of the unique contributions of chromosomal sex, hormone use and lived gender identity. Finally, we will specifically test the sex-differential impact of estrogen signaling on T cell activation and HIV latency reversal, building on our prior studies identifying sex specific characteristics of the HIV latent reservoir. Combined these studies, will provide novel insights into the impact of both sex and gender on the immune response to HIV infection.

项目摘要 生物学性别与HIV免疫发病发生的明显差异有关，但了解有限 这种变化的机制。有1910万妇女和女孩感染艾滋病毒，会计 对于全球艾滋病毒感染的人中有一半以上，但女性通常是少数研究 参与者和性分层的分析并不常见。跨性别妇女承担不成比例的负担 感染，甚至更少的研究试图了解女性性别认同对生物学影响 艾滋病毒感染结果。在动力免疫的机械途径中的性别和性别差异的研究 对感染，病理炎症和HIV库的控制的反应对于发展至关重要 新型治疗干预措施。在此提案中，我们研究生物学和女性性别认同 消除他们对免疫病理学的贡献。具体而言，我们将与广泛的基因组和 国际艾滋病毒基因组学（ICGH）数据集的临床数据分析遗传 性别染色体上HIV疾病进展的决定因素以及在性别分层的分析中 常染色体。我们还将与巴西的Transcendendo队列合作，这是一个由社区投入的人群 跟随个人在出生时分配男性，并与女性生活。我们将为 基于性别良好激素的不同使用，从同类参与者中收集了同类参与者的生物测量 治疗，艾滋病毒感染状况以及包括创伤和抑郁在内的关键协变量的会计。和 免疫转录分析，我们将评估性别认同对免疫激活概况的影响， 了解染色体性别，激素使用和生活性别认同的独特贡献的理解。 最后，我们将专门检验雌激素信号传导对T细胞激活和HIV的性别差异影响 潜伏期逆转，以我们先前的研究为基础，确定了艾滋病毒潜伏储层的性别特定特征。 结合了这些研究，将提供有关性别和性别对免疫影响的影响的新见解 对HIV感染的反应。