title: The role of LAT in increased CD8+ T cell exhaustion in trigeminal ganglia of mice latently infected with herpes simplex virus 1.
abstract: Herpes simplex virus (HSV) infection is a classic example of latent viral infection in humans and experimental animal models. The HSV-1 latency-associated transcript (LAT) plays a major role in the HSV-1 latency reactivation cycle and thus in recurrent disease. Whether the presence of LAT leads to generation of dysfunctional T cell responses in the trigeminal ganglia (TG) of latently infected mice is not known. To address this issue, we used LAT-positive [LAT(+)] and LAT-deficient [LAT(-)] viruses to evaluate the effect of LAT on CD8 T cell exhaustion in TG of latently infected mice. The amount of latency as determined by quantitative reverse transcription-PCR (qRT-PCR) of viral DNA in total TG extracts was 3-fold higher with LAT(+) than with LAT(-) virus. LAT expression and increased latency correlated with increased mRNA levels of CD8, PD-1, and Tim-3. PD-1 is both a marker for exhaustion and a primary factor leading to exhaustion, and Tim-3 can also contribute to exhaustion. These results suggested that LAT(+) TG contain both more CD8(+) T cells and more CD8(+) T cells expressing the exhaustion markers PD-1 and Tim-3. This was confirmed by flow cytometry analyses of expression of CD3/CD8/PD-1/Tim-3, HSV-1, CD8(+) T cell pentamer (specific for a peptide derived from residues 498 to 505 of glycoprotein B [gB(498-505)]), interleukin-2 (IL-2), and tumor necrosis factor alpha (TNF-α). The functional significance of PD-1 and its ligands in HSV-1 latency was demonstrated by the significantly reduced amount of HSV-1 latency in PD-1- and PD-L1-deficient mice. Together, these results may suggest that both PD-1 and Tim-3 are mediators of CD8(+) T cell exhaustion and latency in HSV-1 infection.
authors.affiliation: Center for Neurobiology and Vaccine Development, D2024, Cedars-Sinai Burns and Allen Research Institute, 8700 Beverly Blvd., Los Angeles, CA 90048, USA.
authors.forename: Sariah J
authors.initials: SJ
authors.lastname: Allen
authors.forename: Pedram
authors.initials: P
authors.lastname: Hamrah
authors.forename: David
authors.initials: D
authors.lastname: Gate
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Mott
authors.forename: Dimosthenis
authors.initials: D
authors.lastname: Mantopoulos
authors.forename: Lixin
authors.initials: L
authors.lastname: Zheng
authors.forename: Terrence
authors.initials: T
authors.lastname: Town
authors.forename: Clinton
authors.initials: C
authors.lastname: Jones
authors.forename: Ulrich H
authors.initials: UH
authors.lastname: von Andrian
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Freeman
authors.forename: Arlene H
authors.initials: AH
authors.lastname: Sharpe
authors.forename: Lbachir
authors.initials: L
authors.lastname: BenMohamed
authors.forename: Rafi
authors.initials: R
authors.lastname: Ahmed
authors.forename: Steven L
authors.initials: SL
authors.lastname: Wechsler
authors.forename: Homayon
authors.initials: H
authors.lastname: Ghiasi
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000096:biosynthesis; D016827:CD8 Antigens / Q000096:biosynthesis; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D000072597:Hepatitis A Virus Cellular Receptor 2; D006561:Herpes Simplex / Q000276:immunology* / Q000821:virology; D018259:Herpesvirus 1, Human / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000378:metabolism*; D061026:Programmed Cell Death 1 Receptor; D011991:Receptors, Virus / Q000096:biosynthesis; D012668:Trigeminal Ganglion / Q000276:immunology*; D017735:Virus Latency
chemical_list: D000943:Antigens, Differentiation; D016827:CD8 Antigens; C442241:Havcr2 protein, mouse; D000072597:Hepatitis A Virus Cellular Receptor 2; D035683:MicroRNAs; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D011991:Receptors, Virus; C477253:latency associated transcript, herpes simplex virus-1