Cross-presentation and genome-wide screening reveal candidate T cells antigens for a herpes simplex virus type 1 vaccine

J Clin Invest. 2012 Feb;122(2):654-73. doi: 10.1172/JCI60556. Epub 2012 Jan 3.

Abstract

Herpes simplex virus type 1 (HSV-1) not only causes painful recurrent oral-labial infections, it can also cause permanent brain damage and blindness. There is currently no HSV-1 vaccine. An effective vaccine must stimulate coordinated T cell responses, but the large size of the genome and the low frequency of HSV-1-specific T cells have hampered the search for the most effective T cell antigens for inclusion in a candidate vaccine. We have now developed what we believe to be novel methods to efficiently generate a genome-wide map of the responsiveness of HSV-1-specific T cells, and demonstrate the applicability of these methods to a second complex microbe, vaccinia virus. We used cross-presentation and CD137 activation-based FACS to enrich for polyclonal CD8+ T effector T cells. The HSV-1 proteome was prepared in a flexible format for analyzing both CD8+ and CD4+ T cells from study participants. Scans with participant-specific panels of artificial APCs identified an oligospecific response in each individual. Parallel CD137-based CD4+ T cell research showed discrete oligospecific recognition of HSV-1 antigens. Unexpectedly, the two HSV-1 proteins not previously considered as vaccine candidates elicited both CD8+ and CD4+ T cell responses in most HSV-1-infected individuals. In this era of microbial genomics, our methods - also demonstrated in principle for vaccinia virus for both CD8+ and CD4+ T cells - should be broadly applicable to the selection of T cell antigens for inclusion in candidate vaccines for many pathogens.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antigens, Viral / genetics
  • Antigens, Viral / immunology*
  • CD4-Positive T-Lymphocytes / cytology
  • CD4-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / cytology
  • CD8-Positive T-Lymphocytes / immunology*
  • Cells, Cultured
  • Cross-Priming / immunology*
  • Cytotoxicity, Immunologic / immunology
  • Female
  • HLA Antigens / genetics
  • HLA Antigens / immunology
  • Herpes Simplex / prevention & control
  • Herpesvirus 1, Human / genetics
  • Herpesvirus 1, Human / immunology*
  • Humans
  • Interferon-gamma / immunology
  • Male
  • Middle Aged
  • Tumor Necrosis Factor Receptor Superfamily, Member 9 / immunology
  • Viral Vaccines / immunology*
  • Young Adult

Substances

  • Antigens, Viral
  • HLA Antigens
  • Tumor Necrosis Factor Receptor Superfamily, Member 9
  • Viral Vaccines
  • Interferon-gamma