Understanding HIV Persistence: The Role of Perineural Pathways

New primate data suggest CNS macrophages can carry HIV out of the brain along a perineural route, driving peripheral viral persistence and inflammation despite suppressive antiretroviral therapy.

This finding broadens existing reservoir models that emphasized latent infection in lymphoid tissue and resident microglia by adding a mobile, macrophage-mediated route across neural interfaces. Rather than being sequestered behind the blood–brain barrier, the CNS may seed peripheral compartments via macrophage migration along nerve sheaths and perineural spaces—an active, directional mechanism that could sustain systemic inflammation even with plasma viremia suppressed.

In a nonhuman primate model, the team injected differently colored nanoparticles into cerebrospinal fluid to label CNS macrophages and trace exit pathways; tagged macrophages were later identified along cranial and peripheral nerve sheaths and in downstream peripheral tissues.

Standard ART that suppresses plasma viremia may not eliminate macrophage-mediated reservoirs; strategies that account for myeloid reservoirs and drug penetration into perineural compartments, along with adjunctive anti-inflammatory or myeloid-targeted agents under investigation, warrant translational evaluation rather than immediate practice change.