title: The herpes simplex virus 1 latency-associated transcript promotes functional exhaustion of virus-specific CD8+ T cells in latently infected trigeminal ganglia: a novel immune evasion mechanism.
abstract: Following ocular herpes simplex virus 1 (HSV-1) infection of C57BL/6 mice, HSV-specific (HSV-gB(498-505) tetramer(+)) CD8(+) T cells are induced, selectively retained in latently infected trigeminal ganglia (TG), and appear to decrease HSV-1 reactivation. The HSV-1 latency-associated transcript (LAT) gene, the only viral gene that is abundantly transcribed during latency, increases reactivation. Previously we found that during latency with HSV-1 strain McKrae-derived viruses, more of the total TG resident CD8 T cells expressed markers of exhaustion with LAT(+) virus compared to LAT(-) virus. Here we extend these findings to HSV-1 strain 17syn+-derived LAT(+) and LAT(-) viruses and to a virus expressing just the first 20% of LAT. Thus, the previous findings were not an artifact of HSV-1 strain McKrae, and the LAT function involved mapped to the first 1.5 kb of LAT. Importantly, to our knowledge, we show here for the first time that during LAT(+) virus latency, most of the HSV-1-specific TG resident CD8 T cells were functionally exhausted, as judged by low cytotoxic function and decreased gamma interferon (IFN-γ) and tumor necrosis factor alpha (TNF-α) production. This resulted in LAT(-) TG having more functional HSV-gB(498-505) tetramer(+) CD8(+) T cells compared to LAT(+) TG. In addition, LAT expression, in the absence of other HSV-1 gene products, appeared to be able to directly or indirectly upregulate both PD-L1 and major histocompatibility complex class I (MHC-I) on mouse neuroblastoma cells (Neuro2A). These findings may constitute a novel immune evasion mechanism whereby the HSV-1 LAT directly or indirectly promotes functional exhaustion (i.e., dysfunction) of HSV-specific CD8(+) T cells in latently infected TG, resulting in increased virus reactivation.
authors.affiliation: Laboratory of Cellular and Molecular Immunology, The Gavin Herbert Eye Institute, University of California Irvine, School of Medicine, Irvine, California 92697, USA.
authors.forename: Aziz A
authors.initials: AA
authors.lastname: Chentoufi
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Kritzer
authors.forename: Michael V
authors.initials: MV
authors.lastname: Tran
authors.forename: Gargi
authors.initials: G
authors.lastname: Dasgupta
authors.forename: Chang Hyun
authors.initials: CH
authors.lastname: Lim
authors.forename: David C
authors.initials: DC
authors.lastname: Yu
authors.forename: Rasha E
authors.initials: RE
authors.lastname: Afifi
authors.forename: Xianzhi
authors.initials: X
authors.lastname: Jiang
authors.forename: Dale
authors.initials: D
authors.lastname: Carpenter
authors.forename: Nelson
authors.initials: N
authors.lastname: Osorio
authors.forename: Chinhui
authors.initials: C
authors.lastname: Hsiang
authors.forename: Anthony B
authors.initials: AB
authors.lastname: Nesburn
authors.forename: Steven L
authors.initials: SL
authors.lastname: Wechsler
authors.forename: Lbachir
authors.initials: L
authors.lastname: BenMohamed
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003602:Cytotoxicity, Immunologic; D005260:Female; D018259:Herpesvirus 1, Human / Q000276:immunology* / Q000472:pathogenicity*; D057131:Immune Evasion; D007371:Interferon-gamma / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000378:metabolism*; D012668:Trigeminal Ganglion / Q000821:virology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D017735:Virus Latency
chemical_list: D035683:MicroRNAs; D014409:Tumor Necrosis Factor-alpha; C477253:latency associated transcript, herpes simplex virus-1; D007371:Interferon-gamma