Maintenance of intestinal CX3CR1⁺ macrophage homeostasis defines post-treatment control in SIV-infected macaques

Achieving durable viral remission without antiretroviral therapy (ART) remains a central challenge in HIV-1 cure research. Using a pathogenic SIV model in male cynomolgus macaques, we investigated mucosal and systemic immune features associated with post-treatment control (PTC). Chronic SIV infection disrupts intestinal macrophage homeostasis, skewing the compartment toward a CX3CR1^low inflammatory phenotype marked by increased expression of costimulatory and homing markers. This polarization is associated with mucosal CD4⁺ T cell depletion, elevated neutrophil activation, and systemic cytokine induction. Non-controllers exhibit a similar inflammatory profile. In contrast, PTCs maintain CX3CR1^high macrophages, preserve regulatory CD4 + T cells, and exhibit attenuated mucosal and systemic immune activation, resembling uninfected animals. CX3CR1^high macrophage abundance inversely correlates with viral burden, T cell activation, and pro-inflammatory cytokines, suggesting a potential role in post-treatment control. These findings identify CX3CR1-expressing intestinal macrophages as a potential biomarker of mucosal immune regulation and highlight their relevance as targets in HIV cure strategies.