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Gal-9 and VISTA expression was associated with impaired T cells effector functions. Although Gal-9 was coexpressed with other coinhibitory receptors such as TIGIT, CD160, CD39, and VISTA, it was simultaneously coexpressed with PD-1. Coexpression of Gal-9 with PD-1 was associated with a more terminally exhausted T cell phenotype in HIV-1 patients. This was marked by higher expression of EOMES, blimp1, and Glut1 in Gal-9+ versus Gal-9\u2212 T cells, which is consistent with an exhausted T cell phenotype. Gal-9+ T cells exhibited the phenotype characteristics of effector T cells (CD45RA+, CD45RO-\/lo, CD62L\u2212, CD27lo) with higher T-bet expression. A positive correlation between the plasma viral load with the plasma Gal-9 levels in treatment-naive HIV patients and an inverse correlation between CD4 count with the frequency of CD4+Gal-9+ T cells were observed. Increased percentages of Gal-9+ T cells was evident in HIV-treated patients. Enhanced expression of Gal-9 on T cells following PMA stimulation via protein kinase C suggests persistent TCR stimulation as a potential contributing factor in Gal-9 upregulation in HIV patients. This was supported by the constant degranulation of Gal-9+ T cells. Moreover, CD44 clustering by Gal-9 may influence cytoskeleton rearrangement and coclustering of CD3, which likely impact initiation of signal transduction via TCR. Our preliminary data also confirm upregulation of Gal-9 on T cells in hepatitis B virus and HPV infections. These results demonstrate a novel role for Gal-9 and VISTA in HIV pathogenesis.<\/jats:p>","DOI":"10.4049\/jimmunol.1901481","type":"journal-article","created":{"date-parts":[[2020,3,23]],"date-time":"2020-03-23T22:35:43Z","timestamp":1585002943000},"page":"2474-2491","source":"Crossref","is-referenced-by-count":70,"title":["Galectin-9 and VISTA Expression Define Terminally Exhausted T Cells in HIV-1 Infection"],"prefix":"10.1093","volume":"204","author":[{"given":"Shima","family":"Shahbaz","sequence":"first","affiliation":[{"name":"Department of Dentistry, Faculty of Medicine and Dentistry, University of Alberta , Edmonton, Alberta T6G 2R3 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5170-9533","authenticated-orcid":false,"given":"Garett","family":"Dunsmore","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Immunology, Faculty of Medicine and Dentistry, University of Alberta , Edmonton, Alberta T6G 2R3 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petya","family":"Koleva","sequence":"additional","affiliation":[{"name":"Department of Dentistry, Faculty of Medicine and Dentistry, University of Alberta , Edmonton, Alberta T6G 2R3 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lai","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Dentistry, Faculty of Medicine and Dentistry, University of Alberta , Edmonton, Alberta T6G 2R3 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stan","family":"Houston","sequence":"additional","affiliation":[{"name":"Division of Infectious Disease, Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta , Edmonton, Alberta T6G 2R3 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7215-2009","authenticated-orcid":false,"given":"Shokrollah","family":"Elahi","sequence":"additional","affiliation":[{"name":"Department of Dentistry, Faculty of Medicine and Dentistry, University of Alberta , Edmonton, Alberta T6G 2R3 ,","place":["Canada"]},{"name":"Department of Medical Microbiology and Immunology, Faculty of Medicine and Dentistry, University of Alberta , Edmonton, Alberta T6G 2R3 ,","place":["Canada"]},{"name":"Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta , Edmonton, Alberta T6G 2E1 ,","place":["Canada"]},{"name":"Li Ka Shing Institute of Virology, University of Alberta , Edmonton, Alberta T6G 2E1 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,5,1]]},"reference":[{"key":"2025030417511708500_r1","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.3389\/fimmu.2017.01215","article-title":"Coinhibitory receptor expression and immune checkpoint blockade: maintaining a balance in CD8+ T cell responses to chronic viral infections and cancer","volume":"8","author":"Okoye","year":"2017","journal-title":"Front. 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