Work

Macrophage polarization drives viral reservoirs in HIV-1 infection

Year: 2026

Type: review

Abstract: Macrophages are cells of the myeloid lineage that play a very important role in innate immunity and tissue homeostasis. They have the capacity to respond to aggression from pathogenic agents and are the target of HIV-1 infection via their CD4 receptor and the CCR5 and CXCR4 co-receptors. In People With HIV (PWH), macrophages constitute a virological reservoir, making treatment with Antiretroviral Therapy (ART) difficult as they are resistant to the cytopathic effect induced by the virus, resist apoptosis and are in parts of the body with limited access, such as the brain. During HIV infection, macrophages are activated and polarized with the aim of eliminating the virus. Based on their polarization, they are classified into three main groups during HIV infection: M1 and M4 macrophages, which are classically activated, and M2 macrophages, which are activated alternatively. M2 macrophages are subdivided into several subtypes: M2a, M2b, M2c and M2d. M1 and M4 macrophages are pro-inflammatory and are stimulated by pro-inflammatory cytokines such as IL-2, IL-1r and TNF-α. M2 macrophages are anti-inflammatory and are stimulated by anti-inflammatory cytokines such as IL-4, IL-10 and IL-13. Macrophages constitute a very significant and long-lasting viral reservoir due to their intrinsic longevity. Furthermore, the accumulation of virions within Virus-Containing Compartments (VCCs) maintains the latent virus, thereby demonstrating their role as a critical, stable and long-lasting reservoir. However, the reservoir establishment and the persistence of the virus in polarized macrophages have not been fully explored. In this review, we examined macrophage polarization dynamics during HIV infection and explained how polarized macrophages contribute to the establishment of viral reservoirs. We also discuss how the acquisition of specific phenotypes may be a key factor in HIV reservoir formation. Thus, providing important information to guide reactivation of HIV from macrophages, a critical step in the Shock-and-Kill HIV cure strategy.

Source: Frontiers in Immunology

DOI: 10.3389/fimmu.2026.1941085