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

ABSTRACT: In this study, we investigated the impact of IL15 on the brain’s immune and inflammatory milieu during acute SIV infection of rhesus macaques. Given the ongoing issue of HIV-associated neurocognitive disorders (HAND) in people living with HIV and the role of inflammation in its pathogenesis, understanding the brain’s immune response to lentiviral infections is crucial. We found that SIV infection stimulated a resident brain immune response in control animals, characterized by increased astrocyte activation and enhanced ramification of microbial morphology. However, animals treated with anti-IL15 antibodies (aIL15) prior to SIVmac239X infection showed significantly reduced brain inflammation without altering SIV levels in brain tissues. Specifically, aIL15 treatment resulted in 1) decreased overall microglial cell populations; 2) altered T lymphocyte dynamics in the brain; 3) reduced proinflammatory cytokine (IL6) expression in microglia; and 4) increased anti-inflammatory cytokine (TGF-β) expression in brain macrophages. RNA transcription profiles of aIL15-treated animals revealed an overall reduction in inflammatory signaling, alongside upregulation of genes associated with M1 macrophage signaling pathways. These results suggest that peripheral modulation of IL15 can attenuate neuroinflammation during acute lentiviral infection and may be therapeutic in conditions such as HAND. Our findings highlight the potential for targeting peripheral immune factors to modulate central nervous system inflammation in lentiviral infections.

ORGANISM(S): Macaca mulatta

PROVIDER: GSE310364 | GEO | 2025/11/19

REPOSITORIES: GEO

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Project description:Human immunodeficiency virus (HIV) is widely recognized for its striking impact on the immune system, and it also significantly impacts the central nervous system (CNS). The primary immune constituents in the brain, microglia and macrophages, are the target for HIV in people and the simian immunodeficiency virus (SIV) in nonhuman primates. This infection can lead to neurological dysfunction, known as HIV-associated neurocognitive disorder (HAND) and pathological entities such as HIV-induced encephalitis (HIVE). Given the gaps in our knowledge on how these cells respond in vivo to CNS infection, we performed single-cell multiomic sequencing, including gene expression and ATAC-seq on myeloid cells from the brains of two rhesus macaques with SIV-induced encephalitis (SIVE) as well as two uninfected controls. We used both RNA expression and chromatin accessibility to identify cell clusters. We found that the myeloid cell populations were significantly changed by SIVE, which differed greatly from those found in the uninfected brains. We categorized myeloid cells in the SIVE brains into two primary phenotypes: microglia-like and CAM-like, which were different from each other regarding trancriptomic profile and chromatin accessibility. We found that these microglia-like cells express high levels of chemoattractants for capable of recruiting highly the activated CAM-like cells to the site of infection/inflammation. Additionally, we observed a dramatic shift of upstream gene regulators and their targets in brain myeloid cells during SIVE. The transcription factors (TFs) highly enriched in SIVE-specific cell clusters were related to IRF/STAT and NF-κB mediated interferon and other proinflammatory cytokines production. Interestingly, some of these TF binding sites were also enriched in the open chromatin identified in the SIV DNA provirus in infected myeloid cells, indicating the immune activation in the host cells might also promote HIV/SIV gene expression and regulation . In summary, this study further uncover the trancriptome, gene regulaory events and potenital roles of differenet brain myeloid phenotypes in SIVE.

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

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