The herpes simplex virus 1 encoded latency associated transcript promotes dysfunctional virus specific CD8+ T cells in latently infected trigeminal ganglia (154.39)

Abstract

Abstract Following ocular herpes simplex virus type 1 infection, HSV-specific CD8+ T cells are induced, selectively retained in latently infected trigeminal ganglia and appear to decrease HSV-1 reactivation. The LAT gene increases HSV-1 reactivation. We hypothesized that increased numbers and/or function of HSV-specific functional CD8+ T-cells in TG might be involved in the decreased reactivation seen with LAT(-)mutants. Mice were ocularly infected with either LAT(+) or LAT(-) viruses and the number and function of CD8+ T-cells in TG were examined during latency. Although fewer total CD8+ T-cells were found with LAT(-) viruses, TG had more functional HSV-gB-specific CD8+ T cells compared to LAT(+) TG which had many exhausted HSV-gB-specific CD8+ T cells, as judged by high levels of PD-1, impaired cytotoxicity, and decreased IFN-γ and TNF-α production. In addition, mouse Neuro2A cells expressing LAT, had elevated PD-L1 and MHC-I compared to LAT(-) Neuro2A cells and were resistant to lysis by allogeneic CD8+ T cells. Collectively, our findings suggest that TG from mice latently infected with LAT(-) viruses had more HSV-specific functional CD8+ T-cells than did TG from mice infected with LAT(+) viruses. In addition LAT appeared specifically able to upregulate both PD-L1 and MHC-I. These findings may constitute a novel immune evasion mechanism whereby LAT promotes dysfunctional HSV-specific CD8+ T cells in latently infected TG, resulting in more virus reactivation