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Loss of immune escape mutations during persistent HCV infection in pregnancy enhances replication of vertically transmitted viruses

Nature Medicine volume 19, pages 1529–1533 (2013)Cite this article

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Abstract

Globally, about 1% of pregnant women are persistently infected with the hepatitis C virus (HCV)1. Mother-to-child transmission of HCV occurs in 3–5% of pregnancies2 and accounts for most new childhood infections1,3. HCV-specific CD8+ cytotoxic T lymphocytes (CTLs) are vital in the clearance of acute HCV infections4,5,6, but in the 60–80% of infections that persist, these cells become functionally exhausted or select for mutant viruses that escape T cell recognition7,8,9. Increased HCV replication during pregnancy10,11 suggests that maternofetal immune tolerance mechanisms12 may further impair HCV-specific CTLs, limiting their selective pressure on persistent viruses. To assess this possibility, we characterized circulating viral quasispecies during and after consecutive pregnancies in two women. This revealed a loss of some escape mutations in HLA class I epitopes during pregnancy that was associated with emergence of more fit viruses13. CTL selective pressure was reimposed after childbirth, at which point escape mutations in these epitopes again predominated in the quasispecies and viral load dropped sharply14. Importantly, the viruses transmitted perinatally were those with enhanced fitness due to reversion of escape mutations. Our findings indicate that the immunoregulatory changes of pregnancy reduce CTL selective pressure on HCV class I epitopes, thereby facilitating vertical transmission of viruses with optimized replicative fitness.

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Figure 1: Evolution and relative fitness of M001 E2 CTL escape variants.
Figure 2: Viremia and viral evolution through consecutive episodes of vertical transmission.
Figure 3: Evolution and relative fitness of M003 NS3 CTL escape variants.
Figure 4: Evolution and relative fitness of M003 NS5B CTL escape variants.

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  • 30 May 2014

    In the version of this article initially published, the K1398R/A1409T variant of the 1395–1410 amino acid sequence was erroneously depicted with an arginine in position 1397 in Figure 3a. The correct depiction of the K1398R/A1409T variant should have arginine in position 1398. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank J. Hunkler for coordination of the project at The Ohio State University STEPP Clinic and the Nationwide Children's Hospital FACES Clinic. The assistance of C. Potter of the Nationwide Children's Hospital Division of Gastroenterology and G. Mateu of the Emory Vaccine Center is also gratefully acknowledged. We especially thank the subjects and their families for their participation in this study. This work was supported by the US National Institutes of Health (R37-AI47367 to C.M.W., R56-AI096882 and R01-AI096882 to C.M.W. and J.R.H., RO1-DA024565 and R01-AI95690 to S.M.L., R01-AI070101 and R01-DK083356 to A.G., T32-HD043003 and K12-HD043372 to J.R.H., and the Yerkes Research Center Base Grant P51RR-000165 (A.G.)), the Research Institute at Nationwide Children's Hospital (C.M.W. and J.R.H.), and the University of North Carolina University Cancer Research Fund (S.M.L.).

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Authors and Affiliations

  1. The Center for Vaccines and Immunity, Nationwide Children's Hospital, Columbus, Ohio, USA

    Jonathan R Honegger, Jennifer A Kohout & Christopher M Walker

  2. Department of Pediatrics, The Ohio State University School of Medicine, Columbus, Ohio, USA

    Jonathan R Honegger & Christopher M Walker

  3. Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA

    Seungtaek Kim, Kevin L McKnight & Stanley M Lemon

  4. Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea

    Seungtaek Kim

  5. Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea

    Seungtaek Kim

  6. Division of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia, USA

    Aryn A Price & Arash Grakoui

  7. Department of Obstetrics and Gynecology, The Ohio State University School of Medicine, Columbus, Ohio, USA

    Mona R Prasad

  8. Division of Infectious Diseases, Department of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA

    Stanley M Lemon

  9. Department of Microbiology & Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA

    Stanley M Lemon

  10. Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA

    Arash Grakoui

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Contributions

J.R.H. and C.M.W. conceived of the study; M.R.P. and J.R.H. developed the patient cohort; J.R.H. and J.A.K. designed and conducted T cell experiments and sequenced viral genomes; S.K., A.A.P. and K.L.M. built constructs and conducted viral fitness assays, which A.G. and S.M.L. supervised; J.R.H. wrote the manuscript with editorial input from the other authors.

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Correspondence to Jonathan R Honegger.

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Honegger, J., Kim, S., Price, A. et al. Loss of immune escape mutations during persistent HCV infection in pregnancy enhances replication of vertically transmitted viruses. Nat Med 19, 1529–1533 (2013). https://doi.org/10.1038/nm.3351

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