The DOI matches its Crossref record; 63 of the 63 references it cites were found in a registry or an index.
TIGIT Marks Exhausted T Cells, Correlates with Disease Progression, and Serves as a Target for Immune Restoration in HIV and SIV Infection
Open accessAbstract
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.
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“These include the TIM-3, LAG-3, TIGIT, and B- And T-Lymphocyte-Associated Protein (BTLA) receptors associated with T cell exhaustion as well as VISTA, a receptor found on tumor-infiltrating myeloid cells, whose inhibition promoted anti-tumor immune responses in murine models, and CD96, which has been shown to inhibit NK cell activity in murine cancer models (115–117).”
From Anti-PD-1 and Anti-CTLA-4 Therapies in Cancer: Mechanisms of Action, Efficacy, and Limitations (2018) · cites this paper as [117]
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“These include the TIM-3, LAG-3, TIGIT, and B- And T-Lymphocyte-Associated Protein (BTLA) receptors associated with T cell exhaustion as well as VISTA, a receptor found on tumor-infiltrating myeloid cells, whose inhibition promoted anti-tumor immune responses in murine models, and CD96, which has been shown to inhibit NK cell activity in murine cancer models (115–117).”
From Anti-PD-1 and Anti-CTLA-4 Therapies in Cancer: Mechanisms of Action, Efficacy, and Limitations (2018) · cites this paper as [117]
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Safety, activity, and immune correlates of anti–PD-1 antibody in cancer
Topalian, S. L., Hodi, F. S., Brahmer, J. R., Gettinger, S. N., Smith, D. C., McDermott, D. F., Powderly, J. D., Carvajal, R. D., Sosman, J. A., Atkins, M. B., et al. (2012) · New England Journal of Medicine · doi:10.1056/nejmoa1200690 · Cited by 12,628
Self-citationOncology meets immunology: the cancer-immunity cycle.
Chen, D. S., & Mellman, I. (2013) · Immunity · doi:10.1016/j.immuni.2013.07.012 · Cited by 6,929
Wherry, E. J. (2011) · Nature Immunology · doi:10.1038/ni.2035 · Cited by 4,062 · cited 1×
“During chronic viral infections, high antigenic loads continually stimulate T cells leading to progressive loss of function termed “T cell exhaustion” [1].”
BackgroundThe interaction of TIGIT with PVR and PVRL2 inhibits human NK cell cytotoxicity
Stanietsky, N., Simic, H., Arapovic, J., Toporik, A., Levy, O., Novik, A., Levine, Z., Beiman, M., Dassa, L., Achdout, H., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0903474106 · Cited by 3,524
Safety and Tumor Responses with Lambrolizumab (Anti–PD-1) in Melanoma
Hamid, O., Robert, C., DAUD, A. I., Hodi, F. S., Hwu, W., Kefford, R. F., Wolchok, J. D., Hersey, P., Joseph, R. W., Weber, J. S., et al. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1305133 · Cited by 3,427
PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression
Day, C. L., Kaufmann, D. E., Kiepiela, P., Brown, J. A., Moodley, E. S., Reddy, S., Mackey, E. W., Miller, J. D., Leslie, A. J., DePierres, C., et al. (2006) · Nature · doi:10.1038/nature05115 · Cited by 2,680
MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer
Powles, T. B., Eder, J. P., Fine, G. D., Braiteh, F. S., Loriot, Y., Cruz, C., Joaquim Bellmunt, B., Burris, H. A., Petrylak, D. P., Teng, S.-L. M., et al. (2014) · Nature · doi:10.1038/nature13904 · Cited by 2,410
Blackburn, S. D., Shin, H., Haining, W. N., Zou, T., Workman, C. J., Polley, A., Betts, M. R., Freeman, G. J., Vignali, D. A. A., & Wherry, E. J. (2009) · Nature Immunology · doi:10.1038/ni.1679 · Cited by 2,062
Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction
Trautmann, L., Janbazian, L., Chomont, N., Said, E. A., Gimmig, S., Bessette, B., Boulassel, M.-R., Delwart, E., Sepulveda, H., Balderas, R. S., et al. (2006) · Nature Medicine · doi:10.1038/nm1482 · Cited by 1,565
Memory CD8+ T cells vary in differentiation phenotype in different persistent virus infections
Appay, V., Dunbar, P. R., Callan, M. F. C., Klenerman, P., Gillespie, G. M. A., Papagno, L., Ogg, G. S., King, A., Lechner, F., Spina, C. A., et al. (2002) · Nature Medicine · doi:10.1038/nm0402-379 · Cited by 1,556
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Anti-PD-1 and Anti-CTLA-4 Therapies in Cancer: Mechanisms of Action, Efficacy, and Limitations
Seidel, J. A., Otsuka, A., & Kabashima, K. (2018) · Frontiers in Oncology · doi:10.3389/fonc.2018.00086 · Cited by 1,360
Immune checkpoint blockade in infectious diseases
Wykes, M., & Lewin, S. R. (2017) · Nature reviews. Immunology · doi:10.1038/nri.2017.112 · Cited by 585
TIGIT as an emerging immune checkpoint
Harjunpää, H., & Guillerey, C. (2020) · Clinical and Experimental Immunology · doi:10.1111/cei.13407 · Cited by 552
Immune checkpoints and their inhibition in cancer and infectious diseases
Dyck, L., & Mills, K. H. G. (2017) · European Journal of Immunology · doi:10.1002/eji.201646875 · Cited by 553
CD4+ T Cells Expressing PD-1, TIGIT and LAG-3 Contribute to HIV Persistence during ART
Fromentin, R., Bakeman, W., Lawani, M. B., Khoury, G., Hartogensis, W., DaFonseca, S., Killian, M. L., Epling, L., Hoh, R., Sinclair, E., et al. (2016) · PLoS Pathogens · doi:10.1371/journal.ppat.1005761 · Cited by 418
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Metadata
- Authors
- 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., Sacha, J. B., & Ndhlovu, L. C.
- Affiliations
- University of Hawaiʻi at Mānoa (US)
- Oregon National Primate Research Center (US)
- University of Toronto (CA)
- Tohoku University (JP)
- San Francisco General Hospital (US)
- Bristol-Myers Squibb (United States) (US)
- Corresponding author
- Ndhlovu, Lishomwa C.
- ORCID
- Venue
- PLoS Pathogens
- Publisher
- Public Library of Science (PLoS)
- Published
- 2016-01-07
- Volume
- 12
- Issue
- 1
- Pages
- e1005349
- ISSN
- 1553-7366 (ISSN-L)
- 1553-7374
- PMC
- PMC4704737
- OpenAlex
- W2225639217
- Cited by
- 323
- References
- 63
- Citations by year
- 2026: 10 · 2025: 25 · 2024: 30 · 2023: 33 · 2022: 33 · 2021: 47 · 2020: 44 · 2019: 36 · 2018: 32 · 2017: 18 · 2016: 12
- FWCI
- 22.59
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS Pathogens (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- eScholarship (California Digital Library) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Funders
- Bristol-Myers Squibb
- Oregon Health and Science University (OD011092)
- International AIDS Society
- National Institutes of Health (n01ai085341-004, OD-011092, RR024131, AI027763, NOI-AI-85341, P51OD011092)
- University of California, San Francisco (P30AI027763, UL1RR024131)
- Japan Society for the Promotion of Science (15H04742)
- National Institute of General Medical Sciences (P30GM103341)
- National Institute of Allergy and Infectious Diseases (N01 AI085341, K24AI069994, OD011092, RO1 AI087145, AI027763, RR024131, AI067039, AI069994, AI087145, NOI-AI-85341, HIV-1, R01AI087145, N0I-AI-85341, R24AI067039, P30AI027763)
- National Center for Research Resources (UL1RR024131, RR 024131)
- Office of AIDS Research
- National Institute on Minority Health and Health Disparities (U54MD007584)
- Topics
- Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Keywords
- TIGIT, T cell exhaustion, HIV infection, SIV infection, CD8+ T cells, PD-1, PD-L1, immune checkpoint receptors, disease progression, elite controllers, viral suppression, T cell dysfunction, immune restoration, antibody blocking
- MeSH terms
- Animals, Cell Separation, DNA, Viral, Flow Cytometry, Humans, Lymphocyte Activation, Macaca mulatta, Receptors, Immunologic, RNA, Viral, CD4-Positive T-Lymphocytes, HIV Infections, Simian Acquired Immunodeficiency Syndrome, CD8-Positive T-Lymphocytes, Disease Progression, B7-H1 Antigen
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