The herpes simplex virus latency-associated transcript 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

Persistent pathogens, such as herpes simplex virus 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 or with LAT-rescued mutant (i.e., LAT⁺ TG) is significantly higher than TG latently infected with LATnull mutant (i.e., LAT^- TG). Whether LAT promotes virus reactivation by selectively shaping a unique repertoire of HSV-specific CD8⁺ T cells 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 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⁺ versus LAT- virus. Compared to CD8⁺ T cells from LAT- TG, CD8⁺ T cells from LAT⁺ TG (i) recognized a broader selection of nonoverlapping HSV-1 epitopes, (ii) expressed higher levels of PD-1, TIM-3, and CTLA-4 markers of exhaustion, and (iii) produced less tumor necrosis factor alpha, gamma interferon, and granzyme B. 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.