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

项目总结 携带艾滋病毒的女性可能对慢性艾滋病毒有一种独特的、但目前定义不明确的炎症反应 感染。尽管艾滋病毒携带者的病毒载量通常比艾滋病毒携带者低，但艾滋病毒携带者的女性会失去CD4 T细胞的比例大约是男性的两倍，并且经历了高比例的非艾滋病并存。结果 在这种持续的免疫激活和炎症中，即使在有效的抗逆转录病毒治疗的背景下，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，其中之一 艾滋病毒基础研究中的关键问题不仅是如何治疗艾滋病毒的炎性细胞因子谱 个人与普通人群不同，但这些煽动性特征对女性来说也是不同的 艾滋病毒携带者与艾滋病毒携带者男性相比。在执行这些分析时，还必须 考虑参加接受性肛交。尽管已经确定接受能力强的肛门 性交影响男性队列中的肠道粘膜环境，这种性行为很少被考虑 在对女性的分析中。在这项研究中，我们将重点定义特定性别和特定性行为 HIV感染治疗中全身和肠道炎症的模式，以及微生物和分子的阐明 驱动这些炎症性信号的机制。这将在仔细匹配的种群中进行， 考虑已知的影响循环炎症标志物浓度的因素，如BMI和时机 对女性月经的影响。 在目标1中，我们将量化炎症细胞因子、趋化因子、效应分子、肠道通透性标记物和 HIV感染者血浆和直肠粘膜分泌物中单核细胞活化标志物的研究 关于ART，以及未感染的个人。我们还将量化肠道组织中持续的艾滋病毒复制和 对直肠活检进行批量和空间转录，以开始机械地定义分子 导致肠道慢性炎症的途径。由于已知的接受性肛门的影响 在目标2中，我们将战略性地考虑性行为，并量化 目标1中相同参与者肠道微生物区系的多样性和组成。因此，我们试图定义 性行为中与减少全身和肠道炎症相关的微生物区系的最佳组成 行为特定的方式。在目标3中，我们将利用直肠外植体挑战模型感染直肠活检组织。 由女性和男性捐献，体外，在非荷尔蒙条件下，或在生物上补充雌激素 相关的“低”或“高”浓度。这将使我们能够直接检查i)早期特定性别、特定组织 炎性细胞因子对HIV感染的反应，以及ii)决定雌激素如何影响这些早期反应 回应。并行执行这些多维分析将有助于识别特定性别 应对艾滋病毒感染的炎症模式，从而制定适当的干预措施 减轻这种炎症。

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.