A Narrative Review of Macrophage Plasticity in HIV-1 Persistence: From Tissue Reservoirs to Therapeutic Opportunities

Abstract

Macrophages are key components of the innate immune system and play multifaceted roles in HIV-1 infection. Beyond serving as target cells for HIV-1, macrophages, particularly long-lived tissue-resident populations, are increasingly recognized as contributors to viral persistence during antiretroviral therapy. Macrophages exhibit remarkable plasticity and adopt distinct functional states in response to microenvironmental stimuli, classically categorized as proinflammatory M1 and anti-inflammatory M2 phenotypes. Increasing evidence indicates that dysregulated macrophage polarization is associated with HIV-1 replication, chronic immune activation, and the establishment and maintenance of viral reservoirs. Altered macrophage polarization may modify cytokine production, antiviral responses, cellular survival and immune surveillance, thereby influencing the persistence of HIV-1. Moreover, the broad tissue distribution, long lifespan and relative resistance to virus-induced cytopathic effects of macrophages further complicate the elimination of persistent HIV-1. This review summarizes the regulatory mechanisms of macrophage polarization, discusses its reciprocal interactions with HIV-1 infection, and examines the potential contribution of polarization imbalance to viral reservoir establishment and maintenance. We further discuss the molecular mechanisms underlying the persistence of HIV-1 in macrophages and recent advances in macrophage-targeted therapeutic strategies. Improved understanding of macrophage polarization and its relationship with HIV-1 persistence may inform strategies toward a functional HIV cure.