The overarching goal of this cross-sectional study is to examine if co-morbid heavy alcohol use is associated with innate immune activation and expression of inflammatory genes in HIV-positive, methamphetamine-using men who have sex with men (MSM) treated with anti-retroviral therapy (ART). Chronic activation of the innate immune system and inflammation are independently linked to an excess risk of age-related morbidity and mortality in HIV. This pilot study will examine the relationship of co-morbid heavy drinking with these biological processes using stored specimens from 50 HIV-positive MSM on ART with biologically-confirmed recent methamphetamine use. The primary aim of this study will examine if 25 methamphetamine users with comorbid heavy drinking (METH+ETOH+) display elevations in markers of innate immune activation (i.e., higher soluble CD14 and a greater kynurenine/tryptophan ratio) compared to 25 methamphetamine users without comorbid heavy drinking (METH+ETOH-). A secondary aim of this study is to examine differences in the expression of inflammatory genes (i.e., NFkBp105, IL1B, and TNF) between 25 METH+ETOH+ and 25 METH+ETOH- participants. Findings will advance our understanding of the biological processes whereby methamphetamine use and co-morbid heavy drinking may independently contribute to age-associated morbidity and mortality in HIV. This pilot study will lay the foundation for randomized controlled trials of pharmacologic treatments to mitigate the harmful effects of active polysubstance use and bio-behavioral approaches to the treatment of polysubstance use to optimize health outcomes.