HIV-derived Proteins and Duffy Antigen Receptor for Chemokines Deficiency Promotes Endothelial Dysfunction and Hypertension in Male Mice

HIV affects 39.9 million people globally. Africans and African Americans (AA) are disproportionately affected, accounting for over two-thirds of the people living with HIV (PLWH). While Combination antiretroviral therapy (cART) effectively halts viral replication, viral proteins remain in circulation and contribute to cardiovascular disease (CVD), the leading cause of death among PLWH. Hypertension, the primary risk factor for CVD, affects up to 68% of PLWH in the United States. Africans and AA, regardless of HIV status, exhibit accelerated development of hypertension and CVD compared to Caucasians. Although socioeconomics and health disparities contribute to these racial differences, they do not fully explain them, supporting the contribution of genetic predisposition. Polymorphism in the Duffy antigen receptor for chemokines (DARC), is predominantly prevalent in Africans and AA, and has been associated with heightened systemic inflammation, a key factor in CVD. This study explores how HIV-derived proteins and DARC interact to drive endothelial dysfunction and hypertension. We hypothesize that HIV-derived proteins and DARC deficiency independently and synergistically contribute to endothelial dysfunction and hypertension. To test this, we utilized genetically modified mouse models, including DARC KO, Tg26 transgenic mice expressing HIV proteins, and a novel mouse model expressing HIV proteins on the DARC background (Tg26 DARC KO mice). Vascular reactivity was assessed via wire myography and blood pressure (BP) was measured via tail cuff. Our results show that DARC KO and Tg26 mice exhibit impaired endothelial-dependent relaxation in mesenteric arteries without further impairment in Tg26 DARC KO mice. Smooth muscle cell-dependent relaxation to sodium nitroprusside and contractility to phenylephrine remained intact in all mouse models. Systolic BP was elevated in Tg26, DARC KO, and Tg26 DARC KO mice compared to WT. Pulse wave velocity measurements revealed increased arterial stiffness in Tg26 mice, with no additional effects in DARC KO and Tg26 DARC KO mice. Quantitative PCR analysis of the thoracic aorta and spleen showed increased mRNA expression of inflammatory cytokines CCL2 and TNF-α in DARC KO and Tg26 DARC KO mice compared to WT. To investigate 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. In conclusion, our results suggest that HIV-derived proteins and DARC deficiency contribute to increased inflammation, endothelial dysfunction, and elevated BP in male mice without any synergistic effects between DARC and viral proteins. BMT studies further indicate a clear role in hematopoietic DARC and immune cell-derived proteins in the observed endothelial dysfunction. R01HL147639 R01HL155265 R01AR082307 P01HL1605571 R01HL176323 R01HL175471 T32 HL 155011-3 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.