Simian immunodeficiency virus (SIV) infection of rhesus macaques, a non-natural nonhuman primate (NHP) host for the virus, often leads to an AIDS-like disease, mirroring that caused by HIV in humans. However, SIV is endemic in many African NHPs, termed natural hosts, where the infection is not pathogenic. Baboons are widely distributed African NHPs that do not harbor SIV, but their CD4 T cells are easily infected with SIV ex vivo. In this work, we evaluated an in vivo role for CD8⁺ cells in viral control and applied 17-color flow cytometric and single-cell RNAseq pipelines to characterize immune dynamics that could inform novel therapies for HIV.

Baboons (n=8) were divided into two cohorts: Cohort 1 (C1) received an anti‑CD8α antibody to deplete CD8+ cells, while Cohort 2 (C2) received a control antibody. Both cohorts were then challenged with SIV. CD8+ cell depletion in C1 resulted in viral loads about 100-fold higher than in C2, reaching levels seen in acutely infected rhesus macaques. Viral loads for both cohorts converged to similar levels as CD8+ cells reappeared in C1 at 28 dpi. Minimal changes were seen in the C2 blood CD8 T cell compartment at this timepoint. Interestingly, we observed an increase in the frequency of three clusters of NK8-like cells, all identified as CD3^-CD14^-CD20^-CD8⁺CD95⁺. One cluster, CD16⁺CD69⁺ NK8 cells, expanded from 0.07% to roughly 1% of total leukocytes following peak viremia. Transcriptomic analysis showed that NK8 cells upregulated several antiviral genes (IFI6, MX1, MX2, ISG15, BST2) as well as many uncharacterized noncoding RNAs.

NK8 cells play a critical role in early control of viremia, working in synergy, but perhaps sequentially, with CD8 T cells over the course of acute infection to dampen viremia. As such, baboons hold great promise as a model for investigating innate mechanisms of HIV elite control.