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.