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

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-ß) 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. Overall design: 11 adule male rhesus macaques were used. 8 were infected with SIVmac239. 3 were sacrificed on day 7, 5 were sacrificed on day 14. 3 were uninfected controls. Brain tissue from the frontal cortex and blood was sampled at necropsy. Basal ganglia and thalamus tissue were also collected from one animal.