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

项目总结

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.