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

• Published in: PLoS pathogens Vol. 12; no. 1; p. e1005349
• Main Authors: Chew, Glen M., Fujita, Tsuyoshi, Webb, Gabriela M., Burwitz, Benjamin J., Wu, Helen L., Reed, Jason S., Hammond, Katherine B., Clayton, Kiera L., Ishii, Naoto, Abdel-Mohsen, Mohamed, Liegler, Teri, Mitchell, Brooks I., Hecht, Frederick M., Ostrowski, Mario, Shikuma, Cecilia M., Hansen, Scott G., Maurer, Mark, Korman, Alan J., Deeks, Steven G., Sacha, Jonah B., Ndhlovu, Lishomwa C.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.01.2016; Public Library of Science (PLoS)
• Subjects: Acquired immune deficiency syndrome; AIDS; Animals; B7-H1 Antigen - immunology; CD4-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - immunology; Cell Separation; Development and progression; Disease; Disease Progression; DNA, Viral - analysis; Flow Cytometry; Funding; Health aspects; HIV; HIV infection; HIV Infections - immunology; Host-virus relationships; Human immunodeficiency virus; Humans; Immune response; Infections; Lymphocyte Activation - immunology; Lymphocytes; Macaca mulatta; Mortality; Observations; Receptors, Immunologic - immunology; RNA, Viral - analysis; Simian Acquired Immunodeficiency Syndrome - immunology; Simian immunodeficiency virus; Statistical analysis; T cells; Viral infections
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1005349

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.