Sex, Gender and the Immunopathogenesis of HIV

项目摘要 生物性行为与艾滋病毒免疫致病机制的明显差异有关，但了解有限 这种变异的机制。据统计，有1910万妇女和女孩感染了艾滋病毒 全球略多于一半的艾滋病毒携带者，但女性通常是研究的少数 参与者和性别分层分析并不常见。变性女性背负着不成比例的负担 感染，而更少的研究试图了解女性性别认同对 艾滋病毒感染的后果。免疫机制中的性别和性别差异研究 对感染的反应、病理性炎症和对艾滋病毒宿主的控制对艾滋病的发展至关重要。 新的治疗干预措施。在这项提案中，我们同时调查了生物性别和女性性别认同 以理清它们在免疫病理中的贡献。具体地说，我们将使用广泛的基因组和 国际艾滋病毒基因组学合作(ICGH)数据库中的临床数据以分析基因 性染色体上的HIV疾病进展的决定因素以及在性别分层分析中 常染色体。我们还将与巴西的Transcendo队列合作，这是一个根据社区意见设计的队列 跟踪出生时被指定为男性并与女性生活在一起的人。我们将为 根据性别确认激素的不同用途选择的队列参与者的生物样本收集 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。使用 免疫转录图谱，我们将评估性别认同对免疫激活图谱的影响，以 了解染色体性别、激素使用和活体性别认同的独特贡献。 最后，我们将专门测试雌激素信号对T细胞激活和HIV的性别差异影响 潜伏期逆转，建立在我们之前的研究基础上，确定了艾滋病毒潜伏库的性别特异性特征。 结合这些研究，将为性别和性别对免疫力的影响提供新的见解 对艾滋病毒感染的反应。

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.