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Lbachir BenMohamed, Aziz A. Chentoufi, Michael V. Tran, Elizabeth Krizer, Rash E. Afifi, Nelson Osorio, Xianzhi Jiang, Dale Carpenter, Anthony B. Nesburn, Steven L. Wechsler; The Herpes Simplex Virus-1 Encoded Latency-Associated Transcript Promotes Dysfunctional Virus-Specific CD8+ T Cells in Latently Infected Trigeminal Ganglia: A Novel Immune Evasion Mechanism. Invest. Ophthalmol. Vis. Sci. 2011;52(14):2909.
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Following ocular herpes simplex virus type 1 (HSV-1) infection of mice, HSV-specific CD8+ T cells are induced and selectively retained in latently infected trigeminal ganglia (TG). Experimentally increasing the number of CD8 T-cells in the TG decreases reactivation of latent wild type HSV-1. We therefore hypothesized that increased numbers of HSV-1 specific functional CD8 T-cells in TG might be involved in the decreased reactivation of LAT(-) HSV-1 mutants.
C57BL/6 mice were ocularly infected with LAT(+) or LAT(-) virus and the number and function of CD8 T-cells in TG were examined after latency was established (~35 days post infection). The viral genomic load in latently infected TG is ~2 fold higher with LAT(+) compared to LAT(-) viruses.
Although fewer total CD8 T-cells were found with LAT(-) virus, the LAT(-) TG had more functional HSV-1 specific CD8 T-cells, because most of the HSV-1 specific CD8 T-cells (HSV-gB498-505 tetramer+) from LAT(+) TG were exhausted (dysfunctional) as judged by high levels of PD1, impaired cytotoxicity, and decreased IFN-γ and TNF-α production. In addition, mouse neuroblastoma (Neuro2A) cells transfected with a LAT expressing plasmid, had elevated MHC-1 and PD-L1 compared to the same cells transfected with an empty plasmid and were resistant to lysis by allogeneic CD8+ T cells. Collectively, our findings suggest that TG from mice latently infected with LAT(-) virus had more HSV-1 specific functional CD8 T-cells than did TG from mice latently infected with LAT(+) virus. In addition, even in the absence of other HSV-1 gene products, LAT appeared to directly or indirectly up regulate PD-L1 and MHC-1.
These findings may constitute a novel immune evasion mechanism whereby the HSV-1 LAT, directly or indirectly, promotes dysfunctional virus-specific CD8+ T cells in latently infected TG, which in turn directly or indirectly results in more virus reactivation compared to LAT(-) mutants.
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