Frailty, HIV Infection, Injection Drug Use and the Inflammatory-Microbiome

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PROJECT SUMMARY/ABSTRACT With effective antiretroviral therapy (ART), life expectancy for HIV-infected persons has markedly improved, yet marked deficits in survival remain for HIV-infected persons with a history of injecting drugs (PWID). Disparities among PWID have been attributed in part to a shifting spectrum of disease to aging-associated conditions driven by persistent inflammation even with ART. Frailty is an important aging-related state of vulnerability to stress, with an increased burden in HIV infection, strongly associated with heightened inflammation, and predictive of premature mortality and aging-related morbidity among PWID. Injecting drugs itself can increase the severity of inflammation in HIV. The human gut microbial ecosystem (gut microbiome) critically regulates inflammation and immunity. Alterations in the gut microbiome (gut dysbiosis) together with associated disruptions of gut structure and immune integrity constitute an inflammatory-microbiome signature (gut dysbiosis, increased gut permeability, translocation of microbial products, immune activation, heightened inflammation) linked to adverse aging-associated inflammatory conditions and disease. Proposed is a systematic investigation of the role of HIV infection and injection drug use (IDU) in defining the inflammatory- microbiome signature and determination of the relationship of this signature to frailty. Through assessments of the fecal and mucosal microbiome in the AIDS Linked to the IntraVenous Experience (ALIVE) cohort of HIV- infected and epidemiologically comparable HIV-uninfected PWID, we will determine how HIV infection and active IDU alter microbiome composition and function and the relationship of these changes to inflammation and frailty progression over time. Using a germ free murine model, we will further define the frail human microbial communities and gene products that precipitate inflammation. These studies will facilitate elucidation of gut microbial determinants of frailty among HIV-infected PWID and could significantly inform microbiota modulation strategies to reduce frailty-associated inflammation beyond ART. Understanding the role of the gut microbiome in relation to HIV, injection drug use, and frailty remains a critical next step to reducing the marked disparities in clinical outcomes among HIV-infected PWID.