The role of LAT in increased CD8+ T cell exhaustion in trigeminal ganglia of mice latently infected with herpes simplex virus 1

Sariah J. Allen, Pedram Hamrah, David Gate, Kevin R. Mott, Dimosthenis Mantopoulos, Lixin Zheng, Terrence Town, Clinton Jones, Ulrich H. von Andrian, Gordon J. Freeman, Arlene H. Sharpe, Lbachir BenMohamed, Rafi Ahmed, Steven L. Wechsler, Homayon Ghiasi

Research output: Contribution to journalArticle

71 Scopus citations

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 [gB498-505]), 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.

Original languageEnglish (US)
Pages (from-to)4184-4197
Number of pages14
JournalJournal of virology
Volume85
Issue number9
DOIs
StatePublished - May 2011

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

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    Allen, S. J., Hamrah, P., Gate, D., Mott, K. R., Mantopoulos, D., Zheng, L., Town, T., Jones, C., von Andrian, U. H., Freeman, G. J., Sharpe, A. H., BenMohamed, L., Ahmed, R., Wechsler, S. L., & Ghiasi, H. (2011). The role of LAT in increased CD8+ T cell exhaustion in trigeminal ganglia of mice latently infected with herpes simplex virus 1. Journal of virology, 85(9), 4184-4197. https://doi.org/10.1128/JVI.02290-10