title: 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.
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 LAT-null 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.
  
  
  OBJECTIVE
  A significantly larger repertoire of dysfunctional (exhausted) HSV-specific CD8(+)T cells were found in the TG of HLA transgenic rabbits latently infected with wild-type HSV-1 or with LAT-rescued mutant (i.e., LAT(+)TG) than in a more restricted repertoire of functional HSV-specific CD8(+)T cells in the TG of HLA transgenic rabbits latently infected with LAT-null mutant (i.e., LAT(-)TG). These findings suggest that the HSV-1 LAT locus interferes with the host cellular immune response by shaping a broader repertoire of exhausted HSV-specific CD8(+)T cells within the latency/reactivation TG site.
authors: Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California Irvine, School of Medicine, Irvine, California, USA.
authors: Ruchi
authors: R
authors: Srivastava
authors: Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California Irvine, School of Medicine, Irvine, California, USA.|Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg.
authors: Xavier
authors: X
authors: Dervillez
authors: Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California Irvine, School of Medicine, Irvine, California, USA.
authors: Arif A
authors: AA
authors: Khan
authors: Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California Irvine, School of Medicine, Irvine, California, USA.|Pathology and Clinical Laboratory Medicine, Department of Immunology, King Fahad Medical City, Riyadh, Saudi Arabia.
authors: Aziz A
authors: AA
authors: Chentoufi
authors: Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California Irvine, School of Medicine, Irvine, California, USA.
authors: Sravya
authors: S
authors: Chilukuri
authors: Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California Irvine, School of Medicine, Irvine, California, USA.
authors: Nora
authors: N
authors: Shukr
authors: Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California Irvine, School of Medicine, Irvine, California, USA.
authors: Yasmin
authors: Y
authors: Fazli
authors: Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California Irvine, School of Medicine, Irvine, California, USA.
authors: Nicolas N
authors: NN
authors: Ong
authors: Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California Irvine, School of Medicine, Irvine, California, USA.
authors: Rasha E
authors: RE
authors: Afifi
authors: Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California Irvine, School of Medicine, Irvine, California, USA.
authors: Nelson
authors: N
authors: Osorio
authors: University Laboratory Animal Resources, University of California Irvine, Irvine, California, USA.
authors: Roger
authors: R
authors: Geertsema
authors: Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California Irvine, School of Medicine, Irvine, California, USA.
authors: Anthony B
authors: AB
authors: Nesburn
authors: Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California Irvine, School of Medicine, Irvine, California, USA.|Virology Research, Gavin Herbert Eye Institute and Department of Ophthalmology, University of California Irvine, School of Medicine, Irvine, California, USA.|Department of Microbiology and Molecular Genetics, University of California Irvine, School of Medicine, Irvine, California, USA.|Center for Virus Research, University of California Irvine, Irvine, California, USA.
authors: Steven L
authors: http://orcid.org/0000-0001-8509-5229
authors: SL
authors: Wechsler
authors: Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California Irvine, School of Medicine, Irvine, California, USA lbenmoha@uci.edu.|Department of Molecular Biology and Biochemistry, University of California Irvine, School of Medicine, Irvine, California, USA.|Institute for Immunology, University of California Irvine, School of Medicine, Irvine, California, USA.
authors: Lbachir
authors: L
authors: BenMohamed
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D015870:Gene Expression; D015789:HLA-A2 Antigen / Q000235:genetics / Q000276:immunology*; D018259:Herpesvirus 1, Human / Q000276:immunology*; D006801:Humans; D057131:Immune Evasion; D018655:Lymphocyte Count; D035683:MicroRNAs / Q000235:genetics*; D011817:Rabbits; D012668:Trigeminal Ganglion / Q000276:immunology / Q000821:virology; D017735:Virus Latency
chemical_list: D018984:Epitopes, T-Lymphocyte; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D035683:MicroRNAs; C477253:latency associated transcript, herpes simplex virus-1