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Background People aging with HIV (PAWH) are living longer with effective antiretroviral therapy and new HIV diagnoses are rising in older populations. Concurrent with trends in age, the epidemiology of HIV infection in the United States has shifted geographically and racially; the Southeast and African Americans now have the highest HIV incidence and prevalence. Although there are marked health disparities for rural and African American PAWH, limited data exist comparing aging phenotypes between rural and urban PAWH, and no data exist comparing mechanistic pathways between these populations. Among African American PAWH, we hypothesize that rural PAWH will be more likely than urban PAWH to have a molecular profile of advanced aging associated with chronic disease burden and shorter health span. Methods Demographics, clinical data, and RNA were collected from 14 matched pairs from rural (Wake Forest University, Winston-Salem, NC) and urban cohorts (ALiVE cohort, Johns Hopkins University, Baltimore, MD) matched on age, sex, Short Physical Performance Battery score, smoking status, and sample collection date. Raw sequences were examined for quality, aligned using STAR, and normalized using DESeq2. DESeq2 tested matched pair differential gene expression. Genes with an average read count threshold > 5, a genomic control adjusted P-value < 0.01 and a fold change > 1.3 were retained for further analysis using STRING, MCODE, and IPA to find functional and biological patterns. Results Of the 399 genes meeting significance criteria, 212 showed higher expression in the rural group; the remaining 187 genes showed lower expression in the rural group. Top enriched canonical pathways in the IPA analysis identified differential estrogen signaling (P < 0.0001), inflammation (P < 0.001), and cytokine production (p = 0.005). Protein–protein interactions involved in cell–cell signaling and intracellular trafficking were also differentially identified between the 2 populations. Conclusion Urban and rural PAWH have differential gene expression, particularly centered around estrogen signaling and inflammatory cytokine production. These findings merit further investigation to determine clinical significance, including correlation with phenotypes and healthspan between rural and urban PAWH. Disclosures All authors: No reported disclosures. [ABSTRACT FROM AUTHOR]