Abstract Body: Combination antiretroviral therapy has markedly increased life expectancy in people living with HIV (PLWH) and shifted their primary cause of death from opportunistic to cardiovascular disease (CVD). Africans and individual of African Descent (IAD) are disproportionately affected by HIV, and exhibit accelerated development of hypertension and CVD, independent of their HIV status. Polymorphism in the Duffy antigen receptor for chemokines (DARC), which is associated with heightened HIV infectivity and systemic inflammation due to impaired chemokine clearance, is predominantly prevalent in IAD. To investigate how DARC deficiency interacts with HIV to promote CVD, we used mouse models, either deficient in DARC (DARC KO), constitutively expressing HIV-encoded proteins (Tg26 mouse), or expressing the 2 genetic mutations (Tg26-DARC). We hypothesized that HIV-derived proteins and DARC deficiency independently and synergistically contribute to endothelial dysfunction and hypertension. BP measurements and vascular reactivity studies revealed elevated systolic BP and impaired endothelial-dependent relaxation in Tg26 and DARC KO mice. Tg26 mice exhibited high circulating IL-1α and vascular NOX1 expression, and experiments with neutralizing antibody revealed that vascular dysfunction and hypertension were mediated via an IL-1α/NOX1 mechanism. In contrast, DARC KO mice showed reduced circulating IL-1α and vascular NOX1 levels, but displayed elevated plasma TNFα, IL-1β, and IL-6. Furthermore, DARC-regulated chemokines (CCL2, CCL5, CCR5, CCL7, CXCL2, and CXCL3) were significantly upregulated in CD4+ T cells of DARC KO mice. Interestingly, DARC deficiency in Tg26 mice also led to reduced IL-1α and NOX1, with no additive effect on endothelial function and BP. To examine the role of hematopoietic-expressed DARC and immune cell-derived viral proteins in endothelial dysfunction, we performed bone marrow transplants (BMT). Endothelial-dependent relaxation was impaired in resistance arteries of WT mice receiving DARC KO, Tg26, or Tg26 DARC KO bone marrow. Similarly, systolic BP was significantly elevated in these groups compared to WT to WT transplants. IL-1α was selectively increased in Tg26-WT mice, similar to the donor mice. In conclusion, HIV-derived proteins promote vascular dysfunction through IL-1α/NOX1 signaling, while DARC deficiency contributes to vascular dysfunction through chemokine dysregulation without synergistic effects between DARC and viral proteins.