title: TIGIT Marks Exhausted T Cells, Correlates with Disease Progression, and Serves as a Target for Immune Restoration in HIV and SIV Infection.
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.
authors.affiliation: Hawaii Center for HIV/AIDS, Department of Tropical Medicine, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, United States of America.
authors.forename: Glen M
authors.initials: GM
authors.lastname: Chew
authors.affiliation: Hawaii Center for HIV/AIDS, Department of Tropical Medicine, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, United States of America.|Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Fujita
authors.affiliation: Vaccine and Gene Therapy Institute, Oregon Health and Science University, Portland, Oregon, United States of America.|Oregon National Primate Research Center, Oregon Health and Science University, Portland, Oregon, United States of America.
authors.forename: Gabriela M
authors.initials: GM
authors.lastname: Webb
authors.affiliation: Vaccine and Gene Therapy Institute, Oregon Health and Science University, Portland, Oregon, United States of America.|Oregon National Primate Research Center, Oregon Health and Science University, Portland, Oregon, United States of America.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Burwitz
authors.affiliation: Vaccine and Gene Therapy Institute, Oregon Health and Science University, Portland, Oregon, United States of America.|Oregon National Primate Research Center, Oregon Health and Science University, Portland, Oregon, United States of America.
authors.forename: Helen L
authors.initials: HL
authors.lastname: Wu
authors.affiliation: Vaccine and Gene Therapy Institute, Oregon Health and Science University, Portland, Oregon, United States of America.|Oregon National Primate Research Center, Oregon Health and Science University, Portland, Oregon, United States of America.
authors.forename: Jason S
authors.initials: JS
authors.lastname: Reed
authors.affiliation: Vaccine and Gene Therapy Institute, Oregon Health and Science University, Portland, Oregon, United States of America.|Oregon National Primate Research Center, Oregon Health and Science University, Portland, Oregon, United States of America.
authors.forename: Katherine B
authors.initials: KB
authors.lastname: Hammond
authors.affiliation: Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Kiera L
authors.initials: KL
authors.lastname: Clayton
authors.affiliation: Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Ishii
authors.affiliation: Division of Experimental Medicine, Department of Medicine, San Francisco General Hospital, University of California, San Francisco, San Francisco, California, United States of America.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Abdel-Mohsen
authors.affiliation: Division of Experimental Medicine, Department of Medicine, San Francisco General Hospital, University of California, San Francisco, San Francisco, California, United States of America.
authors.forename: Teri
authors.initials: T
authors.lastname: Liegler
authors.affiliation: Hawaii Center for HIV/AIDS, Department of Tropical Medicine, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, United States of America.
authors.forename: Brooks I
authors.initials: BI
authors.lastname: Mitchell
authors.affiliation: HIV/AIDS Division, Department of Medicine, San Francisco General Hospital, University of California, San Francisco, San Francisco, California, United States of America.
authors.forename: Frederick M
authors.initials: FM
authors.lastname: Hecht
authors.affiliation: Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Mario
authors.initials: M
authors.lastname: Ostrowski
authors.affiliation: Hawaii Center for HIV/AIDS, Department of Tropical Medicine, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, United States of America.
authors.forename: Cecilia M
authors.initials: CM
authors.lastname: Shikuma
authors.affiliation: Vaccine and Gene Therapy Institute, Oregon Health and Science University, Portland, Oregon, United States of America.|Oregon National Primate Research Center, Oregon Health and Science University, Portland, Oregon, United States of America.
authors.forename: Scott G
authors.initials: SG
authors.lastname: Hansen
authors.affiliation: Biologics Discovery California, Bristol-Myers Squibb, Redwood City, California, United States of America.
authors.forename: Mark
authors.initials: M
authors.lastname: Maurer
authors.affiliation: Biologics Discovery California, Bristol-Myers Squibb, Redwood City, California, United States of America.
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Korman
authors.affiliation: HIV/AIDS Division, Department of Medicine, San Francisco General Hospital, University of California, San Francisco, San Francisco, California, United States of America.
authors.forename: Steven G
authors.initials: SG
authors.lastname: Deeks
authors.affiliation: Vaccine and Gene Therapy Institute, Oregon Health and Science University, Portland, Oregon, United States of America.|Oregon National Primate Research Center, Oregon Health and Science University, Portland, Oregon, United States of America.
authors.forename: Jonah B
authors.initials: JB
authors.lastname: Sacha
authors.affiliation: Hawaii Center for HIV/AIDS, Department of Tropical Medicine, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, United States of America.
authors.forename: Lishomwa C
authors.initials: LC
authors.lastname: Ndhlovu
mesh_terms: D000818:Animals; D060890:B7-H1 Antigen / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002469:Cell Separation; D004279:DNA, Viral / Q000032:analysis; D018450:Disease Progression; D005434:Flow Cytometry; D015658:HIV Infections / Q000276:immunology*; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D008253:Macaca mulatta; D012367:RNA, Viral / Q000032:analysis; D011971:Receptors, Immunologic / Q000276:immunology*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology
chemical_list: D060890:B7-H1 Antigen; D004279:DNA, Viral; D012367:RNA, Viral; D011971:Receptors, Immunologic; C534712:TIGIT protein, human