CD8+ lymphocytes modulate acute ZIKV viremia, innate antiviral immunity and tissue dissemination in nonhuman primates

The critical importance of CD8+ lymphocytes during chronic viral infection is well established, but their roles in acute ZIKV infection remain incompletely explored. Importantly, antiviral CD8 responses could modulate neurological manifestations that have accompanied recent ZIKV outbreaks. The rhesus macaque model of ZIKV is a particularly valuable tool to understand immune mechanisms of ZIKV control due to similarities in immune function to humans and due to their susceptibility to infection with primary human isolates of the virus. In the present study, we infected four adult male rhesus macaques with ZIKV, two of which had been depleted of CD8+ lymphocytes prior to infection. CD8 depletion resulted in delayed viremia and a near absence of innate immune responses in the blood, demonstrated by a complete lack of neutrophil recruitment to the blood and a striking absence of transcriptional changes in type I interferon response and other key immune genes relative to non-depleted controls during acute infection. Depletion also resulted in differential patterns of monocyte expansion and reduced monocyte activation measured by CD169 expression. Notably, CD8-depleted macaques showed possible evidence of compensatory CD4 T cell responses and persistence of neutralizing antibodies at later timepoints, despite clearance of virus from serum. Neural lesions were also evident in both CD8-depleted animals. One of the depleted animals recovered CD8+ lymphocytes by 21 days post-infection and mounted a high magnitude CD8 T cell response against the virus. The other CD8-depleted animal did not recover CD8+ lymphocytes over the course of the study, and post-mortem histology revealed severe brainstem encephalomalacia as well as enhanced viral dissemination in the semen and seminal vesicle. Together, these data support a potential role for CD8+ lymphocytes in control of ZIKV dissemination and in maintaining immune regulation during acute infection of rhesus macaques.