Expressed on tissue-resident macrophages, the receptor tyrosine kinase, recepteur d'orgine nantais (RON), functions to maintain inflammation homeostasis by activating genes that promote wound repair and resolve inflammation while repressing genes that perpetuate tissue damage and cell death. Chronic HIV-1 infection is associated with dysregulated inflammation, and we hypothesize that diminished RON expression contributes to the development of end organ diseases such as HIV-1-associated CNS disease. To explore RON function in vivo, we used CNS tissue from a well-characterized SIV macaque model and examined the temporal regulation of RON in the brain during the course of infection. Following prolonged SIV infection, RON expression was inversely correlated with the development of CNS disease; RON was maintained in animals that did not develop CNS lesions and was reduced in SIV-infected macaques that demonstrated moderate to severe inflammatory lesions. Arginase-1 expression was reduced in the brain during late infection, whereas expression of the inflammatory genes, IL-12p40 and TNF-α, was elevated. To validate a role for RON in regulating HIV-1 in primary cells, we used human tissue-resident macrophages isolated from tonsil as a tractable cell model. RON signaling in tissue-resident macrophages, both ligand dependent and independent, limited HIV-1 replication. Furthermore, prolonged HIV-1 infection in vitro resulted in downregulation of RON. We propose a model in which, following chronic HIV-1 infection in the brain, RON expression is decreased, genes that quell inflammation are repressed, and inflammatory mediators are induced to promote tissue inflammation.