TIGIT Marks Exhausted T Cells, Correlates with Disease Progression, and Serves as a Target for Immune Restoration in HIV and SIV Infection
TIGIT Marks Exhausted T Cells, Correlates with Disease Progression, and Serves as a Target for Immune Restoration in HIV and SIV Infection
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.
- University of California, San Francisco United States
- National Oceanic and Atmospheric Administration United States
- Bristol-Myers Squibb (Germany) Germany
- San Francisco General Hospital United States
- Oregon National Primate Research Center United States
CD4-Positive T-Lymphocytes, QH301-705.5, Immunology, Simian Acquired Immunodeficiency Syndrome, 610, HIV Infections, Cell Separation, CD8-Positive T-Lymphocytes, Lymphocyte Activation, Microbiology, B7-H1 Antigen, Clinical Research, Immunologic, Virology, Receptors, 2.1 Biological and endogenous factors, Animals, Humans, Viral, Biology (General), Receptors, Immunologic, Biomedical and Clinical Sciences, DNA, Medical microbiology, RC581-607, Flow Cytometry, Macaca mulatta, Infectious Diseases, Good Health and Well Being, Medical Microbiology, 5.1 Pharmaceuticals, DNA, Viral, Disease Progression, Sexually Transmitted Infections, HIV/AIDS, RNA, RNA, Viral, Immunotherapy, Immunologic diseases. Allergy, Infection, Biotechnology, Research Article
CD4-Positive T-Lymphocytes, QH301-705.5, Immunology, Simian Acquired Immunodeficiency Syndrome, 610, HIV Infections, Cell Separation, CD8-Positive T-Lymphocytes, Lymphocyte Activation, Microbiology, B7-H1 Antigen, Clinical Research, Immunologic, Virology, Receptors, 2.1 Biological and endogenous factors, Animals, Humans, Viral, Biology (General), Receptors, Immunologic, Biomedical and Clinical Sciences, DNA, Medical microbiology, RC581-607, Flow Cytometry, Macaca mulatta, Infectious Diseases, Good Health and Well Being, Medical Microbiology, 5.1 Pharmaceuticals, DNA, Viral, Disease Progression, Sexually Transmitted Infections, HIV/AIDS, RNA, RNA, Viral, Immunotherapy, Immunologic diseases. Allergy, Infection, Biotechnology, Research Article
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