PRINCIPAL INVESTIGATOR: DUERR, ANN C
GRANT NUMBER: R01 DA032106-04S1
ABSTRACT: This administrative supplement will support investigations of the influence of drug and alcohol use, including polysubstance use, on expression of genes involved in innate immunity and cellular activation, two pathways known to affect HIV infection, replication, dissemination and persistence. Our hypothesis is that changes in gene expression associated with drug and alcohol use, especially upregulation of inflammatory pathways including type I and type II IFNs and their downstream targets, impede the development of protective immunity and predispose exposed subjects to infection or poor outcomes after they acquire HIV infection. We currently are enrolling a cohort of 2,000 high-risk HIV-uninfected men who have sex with men (MSM) and transgender women (TW) in Lima, Peru, where there is a concentrated HIV epidemic among MSM/TW (incidence 4.2- 6.2/100 py). High rates of alcohol use disorder (53%), cocaine use (1.5%) or alcohol use disorder plus cocaine use (9.7%) have been documented in this population. We will leverage the infrastructure of our ongoing study to address the following aims. Specific Aim 1: To identify transcriptome signatures associated with drug or alcohol use and polysubstance use. Transcriptome analysis will be conducted to investigate gene expression profiles associated with the use of alcohol or cocaine, or polysubstance abuse (alcohol plus cocaine) using RNA-Seq profiling on whole blood specimens collected at the time of enrollment into the cohort. We will validate the signature we have obtained from cocaine users in the U.S. and extend this signature to our study population using 20 specimens in each of four groups of cohort participants with the following characteristics: cocaine use, alcohol use disorder, cocaine use plus alcohol use disorder, or neither. Specific Aim 2: To collect PBMC specimens to expand the signatures developed in Aim 1 and to allow analysis of the impact of cocaine and alcohol use prior to or at the time of infection on subsequent HIV disease course, including setpoint viral load and the impact on seeding the reservoir. This will include collection and cryopreservation of peripheral blood mononuclear cells (PBMCs) for participants described above (N = 80) and PBMCs for all HIV-infected participants (N = 150) at the time of detection of HIV infection and 6 months later. Significance: The proposed expansion of scope leverages the enrollment of MSM/TW with high rates of AUD, cocaine use and polysubstance to study metabolic and immunologic changes induced by substance use. Specimens will be collected for more detailed transcriptomic and proteomic studies of the relationship of substance use to HIV acquisition and disease course. Ultimately, the inferences gained about potential determinants of susceptibility to HIV infection and poor outcomes after acquisition as well as the environmental factors, such as infection/vaccination, or drug and alcohol use, that cause them will allow the design of more specific prevention interventions.