TIGIT Marks Exhausted T Cells, Correlates with Disease Progression, and Serves as a Target for Immune Restoration in HIV and SIV Infection

Glen M. Chew, Tsuyoshi Fujita, Gabriela M. Webb, Benjamin J. Burwitz, Helen L. Wu, Jason S. Reed, Katherine B. Hammond, Kiera L. Clayton, Naoto Ishii, Mohamed Abdel-Mohsen, Teri Liegler, Brooks I. Mitchell, Frederick M. Hecht, Mario Ostrowski, Cecilia M. Shikuma, Scott G. Hansen, Mark Maurer, Alan J. Korman, Steven G. Deeks, Jonah B. SachaLishomwa C. Ndhlovu

Research output: Contribution to journalArticle

113 Scopus citations

Abstract

HIV infection induces phenotypic and functional changes to CD8+ T cells defined by the coordinated upregulation of a series of negative checkpoint receptors that eventually result in T cell exhaustion and failure to control viral replication. We report that effector CD8+ T cells during HIV infection in blood and SIV infection in lymphoid tissue exhibit higher levels of the negative checkpoint receptor TIGIT. Increased frequencies of TIGIT+ and TIGIT+ PD-1+ CD8+ T cells correlated with parameters of HIV and SIV disease progression. TIGIT remained elevated despite viral suppression in those with either pharmacological antiretroviral control or immunologically in elite controllers. HIV and SIV-specific CD8+ T cells were dysfunctional and expressed high levels of TIGIT and PD-1. Ex-vivo single or combinational antibody blockade of TIGIT and/or PD-L1 restored viral-specific CD8+ T cell effector responses. The frequency of TIGIT+ CD4+ T cells correlated with the CD4+ T cell total HIV DNA. These findings identify TIGIT as a novel marker of dysfunctional HIV-specific T cells and suggest TIGIT along with other checkpoint receptors may be novel curative HIV targets to reverse T cell exhaustion.

Original languageEnglish (US)
Article numbere1005349
JournalPLoS pathogens
Volume12
Issue number1
DOIs
StatePublished - 2016

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Molecular Biology
  • Genetics
  • Virology

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    Chew, G. M., Fujita, T., Webb, G. M., Burwitz, B. J., Wu, H. L., Reed, J. S., Hammond, K. B., Clayton, K. L., Ishii, N., Abdel-Mohsen, M., Liegler, T., Mitchell, B. I., Hecht, F. M., Ostrowski, M., Shikuma, C. M., Hansen, S. G., Maurer, M., Korman, A. J., Deeks, S. G., ... Ndhlovu, L. C. (2016). TIGIT Marks Exhausted T Cells, Correlates with Disease Progression, and Serves as a Target for Immune Restoration in HIV and SIV Infection. PLoS pathogens, 12(1), [e1005349]. https://doi.org/10.1371/journal.ppat.1005349