Defining Sex-Specific Systemic and Gut Inflammatory Profiles in People Living with HIV

项目摘要 感染艾滋病毒的妇女可能对慢性艾滋病毒有一种独特的、但目前尚不明确的炎症反应 感染尽管感染艾滋病毒的妇女的病毒载量通常低于男性，但她们的CD 4+细胞减少。 T细胞的比率大约是男性的两倍，并且非艾滋病合并症的比率很高。因此 这种持续的免疫激活和炎症，即使在有效的抗逆转录病毒治疗，艾滋病- 相关疾病是全世界育龄妇女死亡的主要原因之一。因此， 基础HIV研究的关键问题不仅是治疗的HIV+的炎症细胞因子谱如何改变， 个体与一般人群不同，但这些炎症特征对女性也有不同 与男性艾滋病毒感染者相比，在执行这些分析时，还必须 考虑参与接受性肛交虽然已经确定，接受肛门 性交会影响男性群体的肠道粘膜环境，这种性行为很少被考虑 在女性的分析中。在这项研究中，我们将重点关注性特异性和性行为特异性的定义 治疗HIV感染的全身和肠道炎症模式，并阐明微生物和分子机制， 驱动这些炎症信号的机制。这将在仔细匹配的人群中进行， 考虑到已知影响循环炎症标志物浓度的因素，如BMI和时间 女性的月经。 在目标1中，我们将量化炎症细胞因子、趋化因子、效应分子、肠道通透性标志物和 HIV感染者血浆和直肠粘膜分泌物中的单核细胞活化标志物 以及未受感染的个体。我们还将量化肠道组织内持续的HIV复制， 进行直肠活检的整体和空间转录组学，以开始机械地确定 导致肠道内慢性炎症的途径。由于已知的影响，接受肛门 在目标2中，我们将战略性地考虑性活动，并量化 目标1中招募的相同参与者的肠道微生物群的多样性和组成。因此，我们寻求定义 与减少全身和肠道炎症相关的最佳微生物群组成，在性别和性别 具体的行为方式。在目标3中，我们将利用直肠外植体激发模型感染直肠活检组织 由女性和男性在无激素条件下离体捐赠，或在生物学上补充雌激素 “低”或“高”浓度。这将使我们能够直接检查i）早期性别特异性，组织特异性 炎症细胞因子对HIV感染的反应，和ii）确定雌激素如何影响这些早期的 应答同时进行这些多维分析将有助于确定性别特异性 HIV感染后的炎症模式，从而制定适当的干预措施， 减轻炎症。

Project summary Women living with HIV may have a unique, but currently ill-defined inflammatory response to chronic HIV infection. Despite generally having lower viral loads then men living with HIV, women living with HIV lose CD4+ T cells at approximately twice the rate of men and experience high rates of non-AIDS comorbidities. As a result of this ongoing immune activation and inflammation, even in the setting of effective antiretroviral therapy, AIDS- related illnesses are among the leading causes of death of women of reproductive age, worldwide. Thus, one of the key questions in basic HIV research is not only how the inflammatory cytokine profile of treated HIV+ individuals differs from the general population, but also how these inflammatory profiles are different for women living with HIV as compared to men living with HIV. When performing these analyses, it will be critical to also consider participation in receptive anal intercourse. Though it has been established that receptive anal intercourse influences the gut mucosal environment in cohorts of men, this sexual behavior is rarely considered in analyses among women. In this study, we will focus on defining both sex-specific and sexual behavior-specific patterns of systemic and gut inflammation in treated HIV infection, and elucidating the microbial and molecular mechanisms driving these inflammatory signatures. This will be performed in carefully matched populations, considering factors known to influence circulating inflammatory marker concentrations, such as BMI, and timing of menstruation in women. In Aim 1, we will quantify inflammatory cytokines, chemokines, effector molecules, gut permeability markers, and monocyte activation markers within the plasma and rectal mucosal secretions of men and women living with HIV on ART, as well as uninfected individuals. We will also quantify persistent HIV replication within gut tissue and perform bulk and spatial transcriptomics of rectal biopsies to begin to mechanistically define the molecular pathways contributing to chronic inflammation within the gut. Due to the known influence of receptive anal intercourse on the gut microbiome, in Aim 2, we will strategically consider sexual activity, and quantify the diversity and composition of gut microbiota of the same participants enrolled in Aim 1. Thus, we seek to define optimal composition of microbiota associated with reduced systemic and gut inflammation, in a sex- and sex behavior-specific manner. In Aim 3, we will utilize the rectal explant challenge model to infect rectal biopsies donated by women and men, ex vivo, under ahormonal conditions, or supplemented estrogen at biologically relevant “low” or “high” concentrations. This will allow us to directly examine i) early sex-specific, tissue-specific inflammatory cytokine responses to HIV infection, and ii) determine how estrogen can influence these early responses. Performing these multi-dimensional analyses in parallel will facilitate identification of sex-specific patterns of inflammation in response to HIV infection, and thereby the development appropriate interventions for mitigating this inflammation.