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

定义艾滋病毒感染者的性别特异性全身和肠道炎症特征

• 批准号: 10619980
• 负责人: Colleen F Kelley
• 金额: $ 78.12万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-03 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10619980
• 关键词: Acquired Immunodeficiency Syndrome; Age; Anal Sex; Anti-Retroviral Agents; Automobile Driving; Bacteroides; Basic Science; Biological; Biopsy; Blood; Body mass index; CCL2 gene; CD4 Positive T Lymphocytes; CD80 gene; Cause of Death; Cells; Chronic; Development; Dose; Educational workshop; End stage renal failure; Enterobacteriaceae; Environment; Estradiol; Estrogen Receptors; Estrogens; Future; Gender; General Population; Genes; Genetic Transcription; Gonadal Steroid Hormones; Gut Mucosa; HIV; HIV Infections; HIV Seronegativity; HIV vaccine; IL17 gene; ITGB2 gene; Immune; Immunologics; Immunology; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Inflammatory Response Pathway; Interferons; Intervention; Intestinal permeability; Laboratories; Life; Maintenance; Mediation; Menopause; Menstruation; Modeling; Molecular; Mucositis; Mucous Membrane; Ovulation; Pathology; Pathway interactions; Pattern; Peripheral Blood Mononuclear Cell; Persons; Plasma; Population; Pregnancy; Prevotella; Public Health; Rectum; Reporting; Research; Residual state; Risk; Serum; Sex Behavior; Sex Differences; Shapes; Supplementation; Synapses; TLR4 gene; TNF gene; Tissues; United States National Institutes of Health; Up-Regulation; Variant; Viral; Viral Load result; Viral Pathogenesis; Viral reservoir; Woman; antiretroviral therapy; chemokine; cohort; comorbidity; cytokine; design; dimensional analysis; dysbiosis; experience; gut inflammation; gut microbiome; gut microbiota; immune activation; inflammatory marker; intercellular cell adhesion molecule; men; men who have sex with men; microbial; microbiome; microbiota; monocyte; participant enrollment; pre-exposure prophylaxis; programs; recruit; rectal; reproductive; response; sex; systemic inflammatory response; transcription factor NF-AT c3; transcriptome; transcriptomics; transmission process; vaccine response

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.

项目摘要 患有艾滋病毒的妇女可能对慢性艾滋病毒有独特但目前不确定的炎症反应 感染。尽管病毒载量通常较低，但患有艾滋病毒的男性，艾滋病毒的妇女失去了CD4+ T细胞大约是男性率的两倍，并经​​历了高较高的非AID合并症率。因此 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疗法的情况下， 相关疾病是全球生殖年龄妇女死亡的主要原因之一。那是一个 基本HIV研究中的关键问题不仅是治疗的HIV+的炎症细胞因子概况如何 个体与普通人群不同，但这些炎症性概况的不同而不同 与患有艾滋病毒的男性相比，患有艾滋病毒。进行这些分析时，至关重要 考虑参与接受肛门性交。尽管已经确定了接受肛门 性交影响男人队列中的肠粘膜环境，这种性行为很少被考虑 在女性中的分析中。在这项研究中，我们将专注于定义特定性行为和性行为特定的性行为 治疗的HIV感染中的全身和肠道注射模式，并阐明微生物和分子 驱动这些炎症特征的机制。这将在精心匹配的人群中执行 考虑已知会影响循环炎症标记浓度（例如BMI）的因素和时间安排 妇女月经。 在AIM 1中，我们将量化炎症细胞因子，趋化因子，效应分子，肠道渗透性标记物和 血浆中的单核细胞激活标记和艾滋病毒的男性和女性的直肠粘膜分泌物 关于艺术以及未感染的人。我们还将量化肠道组织内的持续HIV复制 进行直肠活检的批量和空间转录组学开始机械定义分子 导致肠内慢性感染的途径。由于接受肛门的已知影响 关于肠道微生物组的性交，在AIM 2中，我们将在战略上考虑性活动，并量化 参与AIM 1的同一参与者的肠道菌群的多样性和组成。这是我们寻求定义的 与性别和性别减少的全身性和肠道注射相关的微生物群的最佳组成 特定于行为的方式。在AIM 3中，我们将利用直肠外植体挑战模型感染直肠活检 由男性和男性在ahormonal条件下捐赠，或在生物学上补充雌激素 相关的“低”或“高”浓度。这将使我们能够直接检查i）早期性别特异性，特定于组织 炎性细胞因子对HIV感染的反应，ii）确定雌激素如何早期影响这些反应 回答。并行执行这些多维分析将喜欢特定性别的识别 响应艾滋病毒感染的炎症模式，从而开发适当的干预措施 减轻这种炎症。