CD160 and PD-1 co-expression on HIV-specific CD8 T cells defines a subset with advanced dysfunction

PLoS Pathog. 2012;8(8):e1002840. doi: 10.1371/journal.ppat.1002840. Epub 2012 Aug 16.


Chronic viral infections lead to persistent CD8 T cell activation and functional exhaustion. Expression of programmed cell death-1 (PD-1) has been associated to CD8 T cell dysfunction in HIV infection. Herein we report that another negative regulator of T cell activation, CD160, was also upregulated on HIV-specific CD8 T lymphocytes mostly during the chronic phase of infection. CD8 T cells that expressed CD160 or PD-1 were still functional whereas co-expression of CD160 and PD-1 on CD8 T cells defined a novel subset with all the characteristics of functionally exhausted T cells. Blocking the interaction of CD160 with HVEM, its natural ligand, increased HIV-specific CD8 T cell proliferation and cytokine production. Transcriptional profiling showed that CD160(-)PD-1(+)CD8 T cells encompassed a subset of CD8(+) T cells with activated transcriptional programs, while CD160(+)PD-1(+) T cells encompassed primarily CD8(+) T cells with an exhausted phenotype. The transcriptional profile of CD160(+)PD-1(+) T cells showed the downregulation of the NFκB transcriptional node and the upregulation of several inhibitors of T cell survival and function. Overall, we show that CD160 and PD-1 expressing subsets allow differentiating between activated and exhausted CD8 T cells further reinforcing the notion that restoration of function will require multipronged approaches that target several negative regulators.

Publication types

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

MeSH terms

  • Antigens, CD / biosynthesis
  • Antigens, CD / immunology*
  • CD8-Positive T-Lymphocytes / immunology*
  • Cell Differentiation / immunology
  • Cell Proliferation
  • Cell Survival / immunology
  • Cytokines / immunology
  • Cytokines / metabolism
  • Down-Regulation / immunology*
  • Female
  • GPI-Linked Proteins / biosynthesis
  • GPI-Linked Proteins / immunology
  • HIV Infections / immunology*
  • HIV Infections / metabolism
  • HIV-1 / immunology*
  • HIV-1 / metabolism
  • Humans
  • Male
  • NF-kappa B / immunology
  • NF-kappa B / metabolism
  • Programmed Cell Death 1 Receptor / biosynthesis
  • Programmed Cell Death 1 Receptor / immunology*
  • Receptors, Immunologic / biosynthesis
  • Receptors, Immunologic / immunology*
  • Up-Regulation / immunology*


  • Antigens, CD
  • CD160 protein, human
  • Cytokines
  • GPI-Linked Proteins
  • NF-kappa B
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • Receptors, Immunologic