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Research Article

Comprehensive analysis of dengue virus-specific responses supports an HLA-linked protective role for CD8+ T cells

Daniela Weiskopf, Michael A. Angelo, Elzinandes L. de Azeredo, John Sidney, Jason A. Greenbaum, Anira N. Fernando, Anne Broadwater, Ravi V. Kolla, Aruna D. De Silva, Aravinda M. de Silva, Kimberly A. Mattia, Benjamin J. Doranz, Howard M. Grey, Sujan Shresta, Bjoern Peters, and Alessandro Sette
PNAS first published April 11, 2013; https://doi.org/10.1073/pnas.1305227110
Daniela Weiskopf
aDivision of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037;
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Michael A. Angelo
aDivision of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037;
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Elzinandes L. de Azeredo
aDivision of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037;
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John Sidney
aDivision of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037;
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Jason A. Greenbaum
aDivision of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037;
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Anira N. Fernando
bGenetech Research Institute, Colombo 00800, Sri Lanka;
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Anne Broadwater
cDepartment of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, NC 27599; and
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Ravi V. Kolla
aDivision of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037;
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Aruna D. De Silva
aDivision of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037;
bGenetech Research Institute, Colombo 00800, Sri Lanka;
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Aravinda M. de Silva
cDepartment of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, NC 27599; and
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Kimberly A. Mattia
dIntegral Molecular, Philadelphia, PA 19104
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Benjamin J. Doranz
dIntegral Molecular, Philadelphia, PA 19104
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Howard M. Grey
aDivision of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037;
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  • For correspondence: hgrey@liai.org alex@liai.org
Sujan Shresta
aDivision of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037;
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Bjoern Peters
aDivision of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037;
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Alessandro Sette
aDivision of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037;
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  • For correspondence: hgrey@liai.org alex@liai.org
  1. Contributed by Howard M. Grey, March 19, 2013 (sent for review January 22, 2013)

See related content:

  • Original antigenic sin in dengue revisited
    - May 16, 2013
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Significance

Dengue virus is the etiologic agent of dengue fever, the most significant mosquito-borne viral disease in humans, affecting over 100 million individuals each year. Currently there is no licensed vaccine or effective antiviral therapy available, and treatment is largely supportive in nature. This study presents a comprehensive analysis of functional T-cell memory against dengue viruses and suggests an HLA-linked protective role for CD8+ T cells. This demonstration of the protective role of T-cell responses points the way forward to identifying robust correlates of protection in natural immunity and vaccination against dengue virus.

Abstract

The role of CD8+ T cells in dengue virus infection and subsequent disease manifestations is not fully understood. According to the original antigenic sin theory, skewing of T-cell responses induced by primary infection with one serotype causes less effective response upon secondary infection with a different serotype, predisposing individuals to severe disease. A comprehensive analysis of CD8+ responses in the general population from the Sri Lankan hyperendemic area, involving the measurement of ex vivo IFNγ responses associated with more than 400 epitopes, challenges the original antigenic sin theory. Although skewing of responses toward primary infecting viruses was detected, this was not associated with impairment of responses either qualitatively or quantitatively. Furthermore, we demonstrate higher magnitude and more polyfunctional responses for HLA alleles associated with decreased susceptibility to severe disease, suggesting that a vigorous response by multifunctional CD8+ T cells is associated with protection from dengue virus disease.

Footnotes

  • ↵1To whom correspondence may be addressed. E-mail: hgrey{at}liai.org or alex{at}liai.org.
  • Author contributions: D.W., R.V.K., H.M.G., S.S., B.P., and A.S. designed research; D.W., M.A.A., E.L.d.A., J.S., J.A.G., A.N.F., A.B., A.D.D.S., A.M.d.S., K.A.M., B.J.D., and B.P. performed research; A.N.F. and A.D.D.S. contributed new reagents/analytic tools; D.W., M.A.A., E.L.d.A., J.S., J.A.G., A.B., A.M.d.S., K.A.M., B.J.D., H.M.G., B.P., and A.S. analyzed data; and D.W., H.M.G., and A.S. wrote the paper.

  • The authors declare no conflict of interest.

  • Data deposition: A complete list of epitopes is available from the Immune Epitope Database, www.iedb.org (submission ID 1000504).

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1305227110/-/DCSupplemental.

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HLA-linked protective role for CD8+ T cells
Daniela Weiskopf, Michael A. Angelo, Elzinandes L. de Azeredo, John Sidney, Jason A. Greenbaum, Anira N. Fernando, Anne Broadwater, Ravi V. Kolla, Aruna D. De Silva, Aravinda M. de Silva, Kimberly A. Mattia, Benjamin J. Doranz, Howard M. Grey, Sujan Shresta, Bjoern Peters, Alessandro Sette
Proceedings of the National Academy of Sciences Apr 2013, 201305227; DOI: 10.1073/pnas.1305227110

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HLA-linked protective role for CD8+ T cells
Daniela Weiskopf, Michael A. Angelo, Elzinandes L. de Azeredo, John Sidney, Jason A. Greenbaum, Anira N. Fernando, Anne Broadwater, Ravi V. Kolla, Aruna D. De Silva, Aravinda M. de Silva, Kimberly A. Mattia, Benjamin J. Doranz, Howard M. Grey, Sujan Shresta, Bjoern Peters, Alessandro Sette
Proceedings of the National Academy of Sciences Apr 2013, 201305227; DOI: 10.1073/pnas.1305227110
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