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Hepatitis C virus clearance correlates with HLA-DR expression on proliferating CD8+ T cells in immune-primed chimpanzees

Authors

  • Iryna Zubkova,

    1. Laboratory of Hepatitis Viruses, Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD
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  • Hongying Duan,

    1. Laboratory of Hepatitis Viruses, Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD
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  • Frances Wells,

    1. Laboratory of Hepatitis Viruses, Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD
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  • Howard Mostowski,

    1. Office of Cellular and Gene Therapy, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD
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  • Esther Chang,

    1. Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC
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  • Kathleen Pirollo,

    1. Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC
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  • Kris Krawczynski,

    1. Division of Viral Hepatitis, NCHHSTP, Centers for Disease Control and Prevention, Atlanta, GA
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  • Robert Lanford,

    1. Southwest Foundation for Biomedical Research, San Antonio, Texas
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  • Marian Major

    Corresponding author
    1. Laboratory of Hepatitis Viruses, Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD
    • Address reprint requests to: Marian E. Major, Laboratory of Hepatitis Viruses, Division of Viral Products, Bldg. 29A/Rm. 1D10/HFM 448, 8800 Rockville Pike, Bethesda, MD 20892. E-mail: marian.major@fda.hhs.gov; fax: 301-402-5585.

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  • Potential conflict of interest: Dr. Pirollo received grants from SynerGene.

  • Supported by CDC and FDA intramural research funds. The project was supported in part by the appointment of Hongying Duan to the Research Participation Program at CBER administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration.

  • This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

Abstract

Vaccination of chimpanzees against hepatitis C virus (HCV) using T-cell-based vaccines targeting nonstructural proteins has not resulted in the same levels of control and clearance as those seen in animals reexposed after HCV clearance. We hypothesized that the outcome of infection depends on the different subtypes of activated T cells. We used multicolor flow cytometry to evaluate activation (CD38+/HLA-DR+) and proliferation (Ki67+/Bcl-2-low) profiles of CD4+ and CD8+ T cells in peripheral blood before and after challenge in chimpanzees vaccinated using DNA/adenovirus, mock-vaccinated, and chimpanzees that had spontaneously cleared infection (rechallenged). The frequencies of activated or proliferating CD8+ T cells peaked at 2 weeks postchallenge in the vaccinated and rechallenged animals, coinciding with reductions in viral titers. However, the magnitude of the responses did not correlate with outcome or sustained control of viral replication. In contrast, proliferation of the CD8+ T cells coexpressing HLA-DR either with or without CD38 expression was significantly higher at challenge in animals that rapidly cleared HCV and remained so throughout the follow-up period. Conclusion: Our data suggest that the appearance of proliferating HLA-DR+/CD8+ T cells can be used as a predictor of a successfully primed memory immune response against HCV and as a marker of effective vaccination in clinical trials. (Hepatology 2014;59:803–813)

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