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

Ruchi Srivastava, Xavier Dervillez, Arif A. Khan, Aziz A. Chentoufi, Sravya Chilukuri, Nora Shukr, Yasmin Fazli, Nicolas N. Ong, Rasha E. Afifi, Nelson Osorio, Roger Geertsem, Anthony B. Nesburn, Steven L. Wechsler, Lbachir BenMohamed*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

27 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)3913-3928
Number of pages16
JournalJournal of Virology
Volume90
Issue number8
DOIs
Publication statusPublished - 1 Apr 2016

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