Anti-IL-15 treatment reduces acute lentivirus inflammation and signaling in the brain

Daniel R Ram; Raja Mohan Gopalakrishnan; Malika Aid; Kyle Kroll; Jasmine Miftahof; Omar Aristizabal; Eunice Kayitare Gikundiro; Caitlin Davis; Marco M Hefti; Kimberly L Fiock; Brook Tilahun; Yvette Umutoniwase; Kate Loidolt; Christine M Fennessey; Noe B Mercado; Victoria Harper-Alexander; Rhianna Jones; Griffin Woolley; Valerie Varner; Michelle Lifton; Steven E Bosinger; Dan H Barouch; Brandon F Keele; R Keith Reeves; C Sabrina Tan

doi:10.1016/j.xcrm.2025.102567

Anti-IL-15 treatment reduces acute lentivirus inflammation and signaling in the brain

Cell Rep Med. 2026 Jan 20;7(1):102567. doi: 10.1016/j.xcrm.2025.102567. Epub 2026 Jan 9.

Authors

Daniel R Ram¹, Raja Mohan Gopalakrishnan², Malika Aid², Kyle Kroll³, Jasmine Miftahof⁴, Omar Aristizabal⁴, Eunice Kayitare Gikundiro⁵, Caitlin Davis², Marco M Hefti⁶, Kimberly L Fiock⁶, Brook Tilahun⁷, Yvette Umutoniwase⁷, Kate Loidolt⁷, Christine M Fennessey⁸, Noe B Mercado², Victoria Harper-Alexander⁹, Rhianna Jones³, Griffin Woolley³, Valerie Varner², Michelle Lifton², Steven E Bosinger¹⁰, Dan H Barouch², Brandon F Keele⁸, R Keith Reeves¹¹, C Sabrina Tan¹²

Affiliations

¹ Center for Virology and Vaccine Research, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA; Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, USA.
² Center for Virology and Vaccine Research, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
³ Division of Innate and Comparative Immunology, Center for Human Systems Immunology, Duke University School of Medicine, Durham, NC, USA.
⁴ Department of Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
⁵ Center for Virology and Vaccine Research, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA; Department of Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
⁶ Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
⁷ Center for Virology and Vaccine Research, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA; Biology Department, Concordia College, Moorhead, MN, USA.
⁸ AIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
⁹ Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, USA.
¹⁰ Emory Vaccine Center and Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA; Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.
¹¹ Center for Virology and Vaccine Research, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA; Division of Innate and Comparative Immunology, Center for Human Systems Immunology, Duke University School of Medicine, Durham, NC, USA; Division of Surgical Sciences, Department of Surgery, Duke University School of Medicine, Durham, NC, USA.
¹² Center for Virology and Vaccine Research, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA; Department of Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA, USA; Division of Infectious Diseases, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. Electronic address: sabrina-tan@uiowa.edu.

Abstract

HIV-associated neurocognitive disorder (HAND) remains a significant complication in people living with HIV, with inflammation playing a central role in its pathogenesis. Understanding how the brain's immune network responds to lentiviral infection is therefore critical. We show that acute simian immunodeficiency virus (SIV) infection elicits a robust resident brain immune response in control animals, marked by enhanced microglial ramification. In contrast, animals pretreated with anti-interleukin (IL)-15 antibodies (αIL-15) before SIV_mac239X infection display reduced neuroinflammation without altering brain viral burden. Peripheral IL-15 blockade decreases brain-infiltrating T lymphocytes, alters their spatial dynamics, suppresses proinflammatory cytokine (IL-6) expression in microglia, and increases anti-inflammatory cytokine (TGF-β) expression in brain macrophages. Transcriptomic profiling reveals a global reduction in inflammatory signaling and an upregulation of genes associated with M1 macrophage pathways. Together, these findings demonstrate that peripheral IL-15 modulation attenuates neuroinflammation during acute lentiviral infection and highlight IL-15 as a potential therapeutic target for neuroinflammatory conditions of the brain.

Keywords: CNS immune response; HAND; IL-15; SIV; microglia; neuroinflammation.

MeSH terms

Animals
Brain* / drug effects
Brain* / immunology
Brain* / metabolism
Brain* / pathology
Brain* / virology
Inflammation* / drug therapy
Inflammation* / immunology
Inflammation* / pathology
Inflammation* / virology
Interleukin-15* / antagonists & inhibitors
Interleukin-15* / immunology
Interleukin-15* / metabolism
Macaca mulatta
Macrophages / drug effects
Macrophages / immunology
Macrophages / metabolism
Male
Microglia / drug effects
Microglia / immunology
Microglia / metabolism
Signal Transduction* / drug effects
Simian Acquired Immunodeficiency Syndrome* / immunology
Simian Acquired Immunodeficiency Syndrome* / pathology
Simian Acquired Immunodeficiency Syndrome* / virology
Simian Immunodeficiency Virus* / immunology

Substances

Interleukin-15

Abstract

MeSH terms

Substances

Grants and funding