PMID- 26842468 OWN - NLM STAT- MEDLINE DCOM- 20160804 LR - 20181113 IS - 1098-5514 (Electronic) IS - 0022-538X (Print) IS - 0022-538X (Linking) VI - 90 IP - 8 DP - 2016 Apr TI - 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. PG - 3913-3928 LID - 10.1128/JVI.02450-15 [doi] AB - 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. IMPORTANCE: 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. CI - Copyright (c) 2016, American Society for Microbiology. All Rights Reserved. FAU - Srivastava, Ruchi AU - Srivastava R AD - Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California Irvine, School of Medicine, Irvine, California, USA. FAU - Dervillez, Xavier AU - Dervillez X AD - Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California Irvine, School of Medicine, Irvine, California, USA. AD - Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg. FAU - Khan, Arif A AU - Khan AA AD - Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California Irvine, School of Medicine, Irvine, California, USA. FAU - Chentoufi, Aziz A AU - Chentoufi AA AD - Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California Irvine, School of Medicine, Irvine, California, USA. AD - Pathology and Clinical Laboratory Medicine, Department of Immunology, King Fahad Medical City, Riyadh, Saudi Arabia. FAU - Chilukuri, Sravya AU - Chilukuri S AD - Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California Irvine, School of Medicine, Irvine, California, USA. FAU - Shukr, Nora AU - Shukr N AD - Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California Irvine, School of Medicine, Irvine, California, USA. FAU - Fazli, Yasmin AU - Fazli Y AD - Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California Irvine, School of Medicine, Irvine, California, USA. FAU - Ong, Nicolas N AU - Ong NN AD - Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California Irvine, School of Medicine, Irvine, California, USA. FAU - Afifi, Rasha E AU - Afifi RE AD - Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California Irvine, School of Medicine, Irvine, California, USA. FAU - Osorio, Nelson AU - Osorio N AD - Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California Irvine, School of Medicine, Irvine, California, USA. FAU - Geertsema, Roger AU - Geertsema R AD - University Laboratory Animal Resources, University of California Irvine, Irvine, California, USA. FAU - Nesburn, Anthony B AU - Nesburn AB AD - Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California Irvine, School of Medicine, Irvine, California, USA. FAU - Wechsler, Steven L AU - Wechsler SL AUID- ORCID: 0000-0001-8509-5229 AD - Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California Irvine, School of Medicine, Irvine, California, USA. AD - Virology Research, Gavin Herbert Eye Institute and Department of Ophthalmology, University of California Irvine, School of Medicine, Irvine, California, USA. AD - Department of Microbiology and Molecular Genetics, University of California Irvine, School of Medicine, Irvine, California, USA. AD - Center for Virus Research, University of California Irvine, Irvine, California, USA. FAU - BenMohamed, Lbachir AU - BenMohamed L AD - Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California Irvine, School of Medicine, Irvine, California, USA lbenmoha@uci.edu. AD - Department of Molecular Biology and Biochemistry, University of California Irvine, School of Medicine, Irvine, California, USA. AD - Institute for Immunology, University of California Irvine, School of Medicine, Irvine, California, USA. LA - eng GR - EY013191/EY/NEI NIH HHS/United States GR - R01 EY026103/EY/NEI NIH HHS/United States GR - R56 AI098985/AI/NIAID NIH HHS/United States GR - R01 EY013191/EY/NEI NIH HHS/United States GR - EY019896/EY/NEI NIH HHS/United States GR - 1R21AI110902/AI/NIAID NIH HHS/United States GR - R56 AI093133/AI/NIAID NIH HHS/United States GR - R01 EY019896/EY/NEI NIH HHS/United States GR - 1R56AI098985/AI/NIAID NIH HHS/United States GR - R21 AI110902/AI/NIAID NIH HHS/United States GR - EY024618/EY/NEI NIH HHS/United States GR - R01 EY014900/EY/NEI NIH HHS/United States GR - 1R56AI093133/AI/NIAID NIH HHS/United States GR - R01 EY024618/EY/NEI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20160328 PL - United States TA - J Virol JT - Journal of virology JID - 0113724 RN - 0 (Epitopes, T-Lymphocyte) RN - 0 (HLA-A*02:01 antigen) RN - 0 (HLA-A2 Antigen) RN - 0 (MicroRNAs) RN - 0 (latency associated transcript, herpes simplex virus-1) SB - IM MH - Animals MH - Animals, Genetically Modified MH - CD8-Positive T-Lymphocytes/*immunology MH - Epitopes, T-Lymphocyte/immunology MH - Gene Expression MH - HLA-A2 Antigen/genetics/*immunology MH - Herpesvirus 1, Human/*immunology MH - Humans MH - Immune Evasion MH - Lymphocyte Count MH - MicroRNAs/*genetics MH - Rabbits MH - Trigeminal Ganglion/immunology/virology MH - *Virus Latency PMC - PMC4810530 EDAT- 2016/02/05 06:00 MHDA- 2016/08/05 06:00 PMCR- 2016/09/28 CRDT- 2016/02/05 06:00 PHST- 2015/09/24 00:00 [received] PHST- 2016/01/21 00:00 [accepted] PHST- 2016/02/05 06:00 [entrez] PHST- 2016/02/05 06:00 [pubmed] PHST- 2016/08/05 06:00 [medline] PHST- 2016/09/28 00:00 [pmc-release] AID - JVI.02450-15 [pii] AID - 02450-15 [pii] AID - 10.1128/JVI.02450-15 [doi] PST - epublish SO - J Virol. 2016 Mar 28;90(8):3913-3928. doi: 10.1128/JVI.02450-15. Print 2016 Apr.