Background:
Immune responses mounted in the CNS during acute HIV/SIV infection are insufficient to prevent viral seeding and reservoir establishment. The pleiotropic cytokine IL-15 plays a crucial role in anti-viral immune response by stimulating NK and CD8+ T cells to control HIV/SIV infection in blood and tissues. However, the effects of IL-15 on the CNS are largely unknown. Experimental neutralization of IL-15, leading to the depletion of NK and T cells, could significantly influence the viral pathogenesis in the brain, alter reservoir formation, and clarify the role of IL-15 in lentivirus disease. We comprehensively evaluated brain immune and inflammatory responses to acute SIV infection with and without IL-15 neutralization in an established nonhuman primate model.
Methods:
Rhesus macaques(Macaca mulatta) were administered two doses of rhesusized monoclonal antibodies against IL-15(anti-mRh-IL-15) at days -21 and -7 prior to challenge with SIVmac239X(day 0) and necropsied at 7 and 14 days post-infection(dpi). A control group did not receive anti-mRh-IL-15. Peripheral and brain viral load were quantified by qPCR and RNAscope. Sequencing analysis of viral clones were obtained from several brain regions and compared to those in blood and peripheral lymph nodes. CNS histopathology were analyzed by immunohistochemistry in combination with in situ hybridization. Transcriptomic analyses were performed on brain tissue.
Results:
While anti-mRh-IL-15 treatment depleted NK cells from blood and increased virus replication, there was no significant differences in the quantities of SIV RNA or DNA in the brain on either 7 and 14 dpi. Barcoded virus detected in the blood and brain showed clonal expansion restricted to anatomical brain regions. For brain resident cells, peripheral neutralization of IL-15 resulted in increased microglial activation with infection, but decreased the number of astrocytes. While blood T cells were unaltered with IL-15 neutralization, CD8+ T cells decreased in brain, which may have led to an altered balance of local pro- and anti-inflammatory responses, where significantly fewer microglia cells expressed the proinflammatory cytokine – IL-6, and higher numbers of macrophages expressed the anti-inflammatory cytokine- TGF-β.
Conclusions:
IL-15 neutralization altered CNS immune and inflammatory responses to acute SIV infection by decreasing CD8+ T cells and resulting in a tissue environment favoring anti-inflammation, which could overall support the establishment of viral reservoir.