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T-cell Responses to HSV-1 in Persons Who Have Survived Childhood Herpes Simplex Encephalitis

Ott, Mariliis BS*; Jing, Lichen PhD*; Lorenzo, Lazaro MSc; Casanova, Jean-Laurent MD, PhD†‡; Zhang, Shen-Ying MD, PhD†‡; Koelle, David M. MD*§¶‖**

Pediatric Infectious Disease Journal: August 2017 - Volume 36 - Issue 8 - p 741–744
doi: 10.1097/INF.0000000000001631
Original Studies

Background: Herpes simplex encephalitis (HSE) after primary herpes simplex virus (HSV)-1 infection can occur in children due to inborn errors of cell-intrinsic immunity in the central nervous system. Paradoxically, symptomatic mucocutaneous HSV-1 recurrences are rare survivors of childhood HSE. T-cell–acquired immunity is thought to be involved in control of recurrent mucocutaneous HSV infection. We thus tested HSV-1–specific immunity in HSE survivors.

Methods: We obtained serum and peripheral blood mononuclear cells (PBMCs) from participants a median of 13.5 years after HSE. HSV-1 and HSV-2 IgG was detected by type-specific immunoblot. PBMCs from subjects passing quality control criteria were tested using enzyme-linked immunospot assay for CD4 interferon-γ responses with an HSV-1 lysate and for CD8 responses using pooled synthetic HSV-1 peptide CD8 T-cell epitopes. Healthy adult PBMCs were used to standardize assays and as comparators.

Results: All participants were HSV-1 seropositive. Most (23/24) HSE survivors had human leukocyte antigen class I types matching the human leukocyte antigen restriction of the pooled peptides. We detected HSV-specific CD8 T-cell responses in 14 of 24 (58%) HSE survivors and in 9 of 9 healthy HSV-1 seropositive adults. HSV-specific CD4 T-cell responses were present in all 5 HSE subjects tested and in 8 of 9 healthy adults. Response magnitudes were overlapping between subject groups.

Conclusions: The defects in cell-intrinsic immunity leading to failure to control primary central nervous system HSV-1 infection do not preclude the acquisition of specific immunity or the control of recurrent mucocutaneous HSV infections. The rarity and lack of severe or recurrent mucocutaneous HSV infection in survivors of childhood HSE corresponds with intact adaptive T-cell immunity.

From the *Department of Medicine, University of Washington, Seattle, Washington; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, University Paris Descartes, Imagine Institute, Paris 75015, France; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York; §Department of Laboratory Medicine, University of Washington, Department of Global Health, University of Washington, Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, and **Benaroya Research Institute, Seattle, Washington.

Accepted for publication March 2, 2017.

Funded by NIH grant R01AI094019 (to D.M.K.), P01AI031731 (to D.M.K.), 2R01AI088364 (to J-L.C. and S-Y.Z.) and ANR (French National Research Agency) grant HSEIEIER (to S-Y.Z.).

L.J. and D.M.K. are coinventors of patents filed by their employer, University of Washington, concerning HSV vaccines. D.M.K. has received research funding from Admedus, Sanofi Pasteur, Merck and Immune Design Corporation. The other authors have no conflicts of interest to disclose.

Address for correspondence: David M. Koelle, MD, 750 Republican Street, Room E651, Seattle, WA 98109. E-mail:

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