Reports

Noncytotoxic Lytic Granule–Mediated CD8⁺ T Cell Inhibition of HSV-1 Reactivation from Neuronal Latency

Jared E. Knickelbein,^1,2,3 Kamal M. Khanna,^3* Michael B. Yee,³ Catherine J. Baty,^4,5 Paul R. Kinchington,^3,6 Robert L. Hendricks^3,6,7

Reactivation of herpes simplex virus type 1 (HSV-1) from neuronal latency is a common and potentially devastating cause of disease worldwide. CD8⁺ T cells can completely inhibit HSV reactivation in mice, with interferon- affording a portion of this protection. We found that CD8⁺ T cell lytic granules are also required for the maintenance of neuronal latency both in vivo and in ex vivo ganglia cultures and that their directed release to the junction with neurons in latently infected ganglia did not induce neuronal apoptosis. Here, we describe a nonlethal mechanism of viral inactivation in which the lytic granule component, granzyme B, degrades the HSV-1 immediate early protein, ICP4, which is essential for further viral gene expression.

¹ Graduate Program in Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
² Medical Scientist Training Program, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
³ Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
⁴ Center for Biologic Imaging, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
⁵ Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
⁶ Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
⁷ Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.

^* Present address: Department of Immunology, University of Connecticut, Farmington, CT 06030, USA.

To whom correspondence should be addressed. E-mail: hendricksrr{at}upmc.edu

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Immune control of mammalian gamma-herpesviruses: lessons from murid herpesvirus-4.

P. G. Stevenson, J. P. Simas, and S. Efstathiou (2009)
J. Gen. Virol. 90, 2317-2330
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Neuron-Interacting Satellite Glial Cells in Human Trigeminal Ganglia Have an APC Phenotype.

M. van Velzen, J. D. Laman, A. KleinJan, A. Poot, A. D. M. E. Osterhaus, and G. M. G. M. Verjans (2009)
J. Immunol. 183, 2456-2461
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HSV-1-Induced SOCS-1 Expression in Keratinocytes: Use of a SOCS-1 Antagonist to Block a Novel Mechanism of Viral Immune Evasion.

K. G. Frey, C. M. I. Ahmed, R. Dabelic, L. D. Jager, E. N. Noon-Song, S. M. Haider, H. M. Johnson, and N. J. Bigley (2009)
J. Immunol. 183, 1253-1262
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Involvement of CD252 (CD134L) and IL-2 in the Expression of Cytotoxic Proteins in Bacterial- or Viral-Activated Human T Cells.

M. Walch, S. K. Rampini, I. Stoeckli, S. Latinovic-Golic, C. Dumrese, H. Sundstrom, A. Vogetseder, J. Marino, D. L. Glauser, M. van den Broek, et al. (2009)
J. Immunol. 182, 7569-7579
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Fewer Latent Herpes Simplex Virus Type 1 and Cytotoxic T Cells Occur in the Ophthalmic Division than in the Maxillary and Mandibular Divisions of the Human Trigeminal Ganglion and Nerve.

K. Hufner, A. Horn, T. Derfuss, C. Glon, I. Sinicina, V. Arbusow, M. Strupp, T. Brandt, and D. Theil (2009)
J. Virol. 83, 3696-3703
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Loss of Mandibular Lymph Node Integrity Is Associated with an Increase in Sensitivity to HSV-1 Infection in CD118-Deficient Mice.

C. D. Conrady, M. Thapa, T. Wuest, and D. J. J. Carr (2009)
J. Immunol. 182, 3678-3687
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