Deciphering the impact of sex in early subtype C HIV infection and during HART

解读性别对早期 C 亚型 HIV 感染和 HART 期间的影响

• 批准号: 10663367
• 负责人: Eric Hunter
• 金额: $ 84.88万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-11 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10663367
• 关键词: Acute; Age; CD4 Positive T Lymphocytes; CRISPR/Cas technology; Cause of Death; Cells; Cellular Indexing of Transcriptomes and Epitopes by Sequencing; Characteristics; Chronic Phase; Complex; Disease; Disease Outcome; Disease Progression; Disease remission; Dose; Epidemiology; Estradiol; Exhibits; Flow Cytometry; Future; Gene Expression Profile; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Gonadal Steroid Hormones; Grant; Growth; HIV Infections; HIV-1; Hormonal; Immune response; Immunologic Factors; Immunologics; Immunophenotyping; In Vitro; Individual; Infection; Interferon Type I; Interferons; Intervention; Mediating; Molecular; Nature; Outcome; Pathogenesis; Pathway interactions; Peripheral; Peripheral Blood Mononuclear Cell; Phenotype; Population; Predisposing Factor; Predisposition; Premenopause; Production; Reporting; Resolution; Sampling; Sex Differences; Signal Transduction; Source; T-Cell Activation; Technology; Time; Transcript; Up-Regulation; Vial device; Viral; Viral Load result; Virus; Virus Replication; Woman; Zambia; acute infection; antiretroviral therapy; cohort; comorbidity; effective therapy; experimental study; gene function; immune activation; in vivo; latent virus activation; men; recruit; reproductive; response; sex; transcriptome sequencing; transmission process

Current estimates suggest that 17.8 million women are infected with HIV-1 and that it is the leading cause of death in women of reproductive age. However, many studies of HIV-1 transmission and pathogenesis to date have focused on a single sex and are thus unable to directly compare disease course and outcomes between men and women. The initial experiments outlined in this grant utilize samples from a cohort of subtype C HIV-1 acutely infected Zambian men and women that allow for direct comparison of viral, transcriptional and immunologic characteristics between the sexes in individuals with a common genetic background. Paradoxically, even though CD4+ T cells from acutely infected women are significantly more highly activated (CD38+) than in men, women have consistently lower viral load than men, both in the earliest stages and chronic phase of infection. On the other hand, while women exhibit similarly effective levels of viral suppression on antiretroviral treatment (HART), they do bear a greater burden of non-AIDS comorbidities than men. These observations likely result from a complex interaction between a number of viral, hormonal and immunological factors, including the increased production of type I interferons (IFN) in women which can simultaneously cause immune activation as well as restriction of viral replication. In order to understand the molecular basis of these sex-based differences, we propose three Specific Aims: Aim 1: Assess sex-specific differences in immunological and transcriptional profiles of CD4+ T cells in early infection. Aim 2: In ART-suppressed women and men, define the landscape of immune cell activation, the nature of the latent reservoir, and its potential for reactivation in the presence and absence of sex hormones. Aim 3: Define the mechanism and cell source of sex hormone modulation of viral replication in vitro. The proposed experiments will fill a significant gap in our understanding of the mechanisms underlying observed differences in HIV-1 disease course and comorbidities between men and women, an important question at a time when sex differences are clearly defining distinct disease outcomes in various disease settings.

目前的估计表明，有 1780 万女性感染了 HIV-1，这是艾滋病毒感染的主要原因。 育龄妇女死亡。然而，迄今为止，许多关于 HIV-1 传播和发病机制的研究 专注于单一性别，因此无法直接比较不同性别之间的疾病过程和结果 男女。本次资助中概述的初步实验利用了 C 亚型 HIV-1 队列的样本 急性感染的赞比亚男性和女性，可以直接比较病毒、转录和 具有共同遗传背景的个体的性别之间的免疫学特征。 矛盾的是，尽管来自急性感染女性的 CD4+ T 细胞的激活程度明显更高 (CD38+) 与男性相比，女性的病毒载量始终低于男性，无论是在最早阶段还是在 感染的慢性期。另一方面，虽然女性表现出同样有效的病毒抑制水平 在抗逆转录病毒治疗（HART）方面，她们确实比男性承受着更大的非艾滋病合并症负担。这些 观察结果可能是多种病毒、激素和免疫学之间复杂相互作用的结果 因素，包括女性体内 I 型干扰素 (IFN) 的产生增加，这可以同时 引起免疫激活以及病毒复制的限制。为了了解其分子基础 针对这些基于性别的差异，我们提出了三个具体目标： 目标 1：评估 CD4+ T 细胞免疫学和转录谱的性别特异性差异 早期感染。 目标 2：在受 ART 抑制的女性和男性中，定义免疫细胞激活的情况、性质 潜在储存库的情况，及其在存在和不存在性激素的情况下重新激活的潜力。 目标3：明确性激素调节体外病毒复制的机制和细胞来源。 所提出的实验将填补我们对潜在机制理解的重大空白 观察到男性和女性之间 HIV-1 病程和合并症的差异，这是一个重要的 在性别差异清楚地定义各种疾病的不同疾病结果之际提出这个问题 设置。