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Chronic inflammation persists in PWH despite viral suppression with antiretroviral therapy and contributes to high rates of cardiometabolic comorbidities. This is partly due to dysregulated leukocyte trafficking and endothelial activation. This review synthesizes preclinical, genetic, and clinical evidence on the multifaceted roles of CX3CR1 across immune, vascular, and cardiometabolic processes. CX3CR1 is expressed on monocyte and cytotoxic T cell subsets implicated in endothelial injury, tissue trafficking, and plaque progression. On the other hand, CX3CL1 is expressed on activated endothelial and stromal cells, which promotes leukocyte adhesion and recruitment into inflamed tissues. In PWH, persistent immune activation and cytomegalovirus coinfections are associated with the expansion of differentiated CX3CR1-expressing T cell populations, supporting the relevance of this pathway to HIV-associated inflammatory comorbidities. At the genetic level, CX3CR1 polymorphisms, including V249I and T280M, alter receptor signaling and have been associated with HIV disease progression and cardiovascular disease risk, highlighting CX3CR1 as both a biomarker and potential mediator of immune-driven pathology. Across preclinical models, pharmacological targeting of CX3CR1 or CX3CL1 attenuates inflammation, fibrosis, and vascular injury in the selected disease contexts. However, the effects of CX3CR1 signaling are tissue- and cell type-specific, and blockade may carry potential risks in settings where CX3CR1 supports immune surveillance, mucosal repair, or macrophage homeostasis. 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