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Anti-IL-15 treatment reduces acute lentivirus inflammation and signaling in the brain
Journal article   Open access   Peer reviewed

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, …
Cell reports. Medicine, Vol.7(1), 102567
01/20/2025
DOI: 10.1016/j.xcrm.2025.102567
PMCID: PMC12866110
PMID: 41519130
url
https://doi.org/10.1016/j.xcrm.2025.102567View
Published (Version of record) Open Access

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 SIVmac239X 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. [Display omitted] •Peripheral pre-administration of αIL-15 alters CNS immune responses to acute SIV infection•T cell quantities in the brain are reduced following peripheral αIL-15•Pre-treatment with αIL-15 prior to SIV infection does not alter brain viral load•Blood IL-15 quantities and elevated T cells are linked to M2 microglia phenotype in brain Ram and Gopalakrishnan et al. demonstrate that peripheral cytokine modulation alters the brain’s inflammatory environment and immune response to retroviral infection. These results demonstrate that a favorable central nervous system environment can be induced by intravenous administrations of antibodies. This work will inform and guide therapeutic strategies for HIV-associated neurocognitive disorder.
 CNS immune response HAND IL-15 microglia neuroinflammation SIV

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