Researchers Identify Perineural Pathway That Fuels HIV Persistence Despite Treatment

Addressing the question of whether and how immune cells (macrophages) in the central nervous system (CNS) traffic out, researchers have now identified a perineural pathway through which the HIV virus can redistribute throughout the body. The findings from a study in The American Journal of Pathology, published by Elsevier, shed light on how these cells travel from the brain through the body, reseeding HIV and sustaining inflammation despite treatment with antiretroviral therapy.

The CNS has long been considered anatomically and immunologically segregated from the rest of the body because of the presence of tight junctions, the perception of limited draining lymphatics, and the presence of the blood-brain barrier. However, the connection between the CNS and the peripheral nervous system (PNS, outside the blood-brain barrier) is often overlooked and not well understood.

Co-lead investigator Kenneth C. Williams, PhD, Morrissey College of Arts and Sciences, Biology Department, Boston College, explains, “In a monkey model of HIV, we injected two different colored nanoparticles directly into the cerebrospinal fluid—the protective liquid of the brain and spinal cord. These particles effectively labeled the CNS macrophages upon absorption. By using distinct colors, we could mark macrophages at different stages of infection—early versus late—and subsequently determine the specific routes these tagged cells used to exit the CNS.”

“Not only did we discover that the macrophages can leave under noninfection conditions, but we also found that they exit via cranial and peripheral nerves,“ adds co-lead investigator Robert V. Blair, PhD, DVM, Tulane National Primate Research Center.

The CNS is recognized as a critical reservoir for viruses such as HIV and its monkey-equivalent SIV (Simian Immunodeficiency Virus), with perivascular macrophages being the primary HIV- and SIV-infected cells in the CNS. The new understanding of immune cell movement uncovered by this study reveals that this reservoir is not static but actively contributes to persistent viral activity and inflammation throughout the body.

“These results underline the importance of the connection between the CNS and PNS in immunity, particularly the impact of macrophage traffic on persistent myeloid activation in the dorsal root ganglia and peripheral nerves. Our findings provide critical insights that will inform new strategies in the challenge of eradicating HIV,” concludes co-lead investigator Zoey K. Wallis, PhD, Morrissey College of Arts and Sciences, Biology Department, Boston College.

Notes for editors

The article is “Novel Perineural Pathways and the Dynamics of SIV-Infected Macrophage Trafficking Out of the Central Nervous System,” by Zoey K. Wallis, Yingshan Wei, Lily M. Ceraso, Cecily C. Midkiff, Addison Q. Amadeck, Yiwei Wang, Andrew D. Miller, Robert V. Blair, and Kenneth C. Williams (https://doi.org/10.1016/j.ajpath.2025.07.014). It appears in The American Journal of Pathology, volume 195, issue 11 (November 2025), published by Elsevier.

The article is openly available for 30 days at https://ajp.amjpathol.org/article/S0002-9440(25)00325-6/fulltext.

This study was supported in part by NIH grants RO1NS126091 and RO1NS040237.

Full text of the article is also available to credentialed journalists upon request. Contact Eileen Leahy at +1 732 406 1313 or [email protected] to request a PDF of the article or more information. To reach the study’s authors, contact Kenneth C. Williams, PhD, at [email protected], or Robert V. Blair, PhD, DVM, at [email protected].

About The American Journal of Pathology

The American Journal of Pathology, official journal of the American Society for Investigative Pathology, published by Elsevier, seeks high-quality original research reports, reviews, and commentaries related to the molecular and cellular basis of disease. The editors will consider basic, translational, and clinical investigations that directly address mechanisms of pathogenesis or provide a foundation for future mechanistic inquiries. Examples of such foundational investigations include data mining, identification of biomarkers, molecular pathology, and discovery research. High priority is given to studies of human disease and relevant experimental models using molecular, cellular, and organismal approaches. ajp.amjpathol.org

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