The Herpes Simplex Virus LAT Gene is Associated with a Broader Repertoire of Virus-Specific Exhausted CD8+ T Cells Retained Within The Trigeminal Ganglia of Latently Infected HLA Transgenic Rabbits

Abstract

Abstract Persistent pathogens, such as herpes simplex virus type 1 (HSV-1), have evolved a variety of immune evasion strategies to avoid being detected and destroyed by the host’s immune system. A dynamic cross talk appears to occur between the HSV-1 Latency-Associated Transcript (LAT), the only viral gene that is abundantly transcribed during latency, and the CD8+ T cells that reside in HSV-1 latently infected human and rabbit trigeminal ganglia (TG). The reactivation phenotype of TG that are latently infected with wild type HSV-1 (i.e. LAT(+) TG) is significantly higher than TG latently infected with LAT null mutant (i.e. LAT(−) TG). Whether LAT promotes virus reactivation by selectively shaping a unique repertoire of HSV-specific CD8+ T cells retained in LAT(+) TG is unknown. In the present study, we assessed the frequency, function, and exhaustion status of TG-resident CD8+ T cells specific to 40 different epitopes derived from HSV-1 gB, gD, VP11/12 and VP13/14 proteins, in Human Leukocyte Antigen (HLA-A*0201) transgenic rabbits infected ocularly with LAT(+) vs. LAT(−) virus. Compared to CD8+ T cells from LAT(−) TG, CD8+ T cells from LAT(+) TG: (i) recognized a broader selection of non-overlapping HSV-1 epitopes; (ii) expressed higher levels of PD-1, TIM-3 and CTLA-4 markers of exhaustion; and (iii) produced less TNF-a, IFN-g, and GzmB. These results suggest a novel immune evasion mechanism by which the HSV-1 LAT may contribute to the shaping of a broader repertoire of exhausted HSV-specific CD8+ T cells in latently infected TG, thus, allowing for increased viral reactivation.