Whether heavy alcohol consumption accelerates HIV disease progression is a fundamental unanswered question with far-reaching public health implications. Alcohol is one of the most commonly used drugs in the world, and heavy alcohol consumption is very common among those infected with HIV. Animal studies suggest that heavy alcohol consumption early in infection has the potential to accelerate HIV disease progression. However, the results of human observational studies of alcohol consumption on HIV disease progression, beyond the effect on antiretroviral therapy (ART) adherence, have been much less consistent due to several methodological limitations. We propose a 650-person prospective cohort study to examine the effect of heavy alcohol consumption on HIV disease progression prior to ART. We will conduct this research in Uganda, which has very high levels of alcohol consumption, high prevalence of HIV infection, and many HIV-infected persons not yet on ART. Participants, studied prospectively, will be recruited from an 8,000 patient HIV treatment program in Uganda as an expansion of a newly initiated 210 person prospective cohort study. The main goal is to determine the impact of heavy alcohol consumption on HIV disease progression, as measured by CD4 cell count decline among those not yet on ART. We will overcome previous methodological limitations by limiting our study to those not on ART, by using a biomarker of alcohol consumption, phosphatidylethanol (PEth), to correctly assess alcohol consumption, and by conducting the study in Uganda, where other substance use is rare. We will conduct exploratory analyses of several biological and behavioral pathways by which heavy alcohol consumption may accelerate HIV disease progression. In conducting this study, we will gain critical evidence of the impact of heavy alcohol use on the clinical course of HIV infection among persons not on ART that will provide clinicians and patients with clear information and may provide motivation to reduce alcohol consumption earlier than previously thought necessary, both in the US and around the world. In addition, better understanding of the mechanisms by which alcohol-induced damage occurs will inform the development of effective interventions. PUBLIC HEALTH RELEVANCE: A high percentage of HIV infected persons consume alcohol, yet due to the limitations of previous research, it is still unknown whether heavy alcohol consumption accelerates HIV disease progression prior to the start of ART. This study will provide clear evidence about the value of decreasing alcohol consumption early in HIV infection, rather than waiting until ART is initiated, as is the current practice.