title: CD4+ T Cells Expressing PD-1, TIGIT and LAG-3 Contribute to HIV Persistence during ART.
abstract: HIV persists in a small pool of latently infected cells despite antiretroviral therapy (ART). Identifying cellular markers expressed at the surface of these cells may lead to novel therapeutic strategies to reduce the size of the HIV reservoir. We hypothesized that CD4+ T cells expressing immune checkpoint molecules would be enriched in HIV-infected cells in individuals receiving suppressive ART. Expression levels of 7 immune checkpoint molecules (PD-1, CTLA-4, LAG-3, TIGIT, TIM-3, CD160 and 2B4) as well as 4 markers of HIV persistence (integrated and total HIV DNA, 2-LTR circles and cell-associated unspliced HIV RNA) were measured in PBMCs from 48 virally suppressed individuals. Using negative binomial regression models, we identified PD-1, TIGIT and LAG-3 as immune checkpoint molecules positively associated with the frequency of CD4+ T cells harboring integrated HIV DNA. The frequency of CD4+ T cells co-expressing PD-1, TIGIT and LAG-3 independently predicted the frequency of cells harboring integrated HIV DNA. Quantification of HIV genomes in highly purified cell subsets from blood further revealed that expressions of PD-1, TIGIT and LAG-3 were associated with HIV-infected cells in distinct memory CD4+ T cell subsets. CD4+ T cells co-expressing the three markers were highly enriched for integrated viral genomes (median of 8.2 fold compared to total CD4+ T cells). Importantly, most cells carrying inducible HIV genomes expressed at least one of these markers (median contribution of cells expressing LAG-3, PD-1 or TIGIT to the inducible reservoir = 76%). Our data provide evidence that CD4+ T cells expressing PD-1, TIGIT and LAG-3 alone or in combination are enriched for persistent HIV during ART and suggest that immune checkpoint blockers directed against these receptors may represent valuable tools to target latently infected cells in virally suppressed individuals.
authors.affiliation: Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Rémi
authors.initials: R
authors.lastname: Fromentin
authors.affiliation: Vaccine and Gene Therapy Institute Florida, Port St Lucie, Florida, United States of America.
authors.forename: Wendy
authors.initials: W
authors.lastname: Bakeman
authors.affiliation: Vaccine and Gene Therapy Institute Florida, Port St Lucie, Florida, United States of America.
authors.forename: Mariam B
authors.initials: MB
authors.lastname: Lawani
authors.affiliation: Department of Infectious Diseases, Monash University and Alfred Hospital, Melbourne, Victoria, Australia.|The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Victoria, Australia.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Khoury
authors.affiliation: Department of Epidemiology and Biostatistics, University of California, San Francisco, California, United States of America.
authors.forename: Wendy
authors.initials: W
authors.lastname: Hartogensis
authors.affiliation: Vaccine and Gene Therapy Institute Florida, Port St Lucie, Florida, United States of America.
authors.forename: Sandrina
authors.initials: S
authors.lastname: DaFonseca
authors.affiliation: Department of Medicine, University of California, San Francisco, California, United States of America.
authors.forename: Marisela
authors.initials: M
authors.lastname: Killian
authors.affiliation: Department of Medicine, University of California, San Francisco, California, United States of America.
authors.forename: Lorrie
authors.initials: L
authors.lastname: Epling
authors.affiliation: Department of Medicine, University of California, San Francisco, California, United States of America.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Hoh
authors.affiliation: Department of Medicine, University of California, San Francisco, California, United States of America.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Sinclair
authors.affiliation: Department of Medicine, University of California, San Francisco, California, United States of America.
authors.forename: Frederick M
authors.initials: FM
authors.lastname: Hecht
authors.affiliation: Department of Epidemiology and Biostatistics, University of California, San Francisco, California, United States of America.
authors.forename: Peter
authors.initials: P
authors.lastname: Bacchetti
authors.affiliation: Department of Medicine, University of California, San Francisco, California, United States of America.
authors.forename: Steven G
authors.initials: SG
authors.lastname: Deeks
authors.affiliation: Department of Infectious Diseases, Monash University and Alfred Hospital, Melbourne, Victoria, Australia.|The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Victoria, Australia.
authors.forename: Sharon R
authors.initials: SR
authors.lastname: Lewin
authors.affiliation: Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: Rafick-Pierre
authors.initials: RP
authors.lastname: Sékaly
authors.affiliation: Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada.|Vaccine and Gene Therapy Institute Florida, Port St Lucie, Florida, United States of America.|Department of Microbiology, Infectiology, and Immunology, Université de Montréal, Faculty of Medicine, Montreal, Quebec, Canada.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Chomont
mesh_terms: D044966:Anti-Retroviral Agents; D015703:Antigens, CD / Q000096:biosynthesis; D015415:Biomarkers / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000821:virology*; D002469:Cell Separation; D003430:Cross-Sectional Studies; D005260:Female; D015658:HIV Infections / Q000276:immunology / Q000378:metabolism / Q000821:virology*; D015497:HIV-1 / Q000276:immunology; D006801:Humans; D016130:Immunophenotyping; D008297:Male; D008875:Middle Aged; D061026:Programmed Cell Death 1 Receptor / Q000096:biosynthesis; D011971:Receptors, Immunologic / Q000096:biosynthesis; D016176:T-Lymphocyte Subsets / Q000378:metabolism / Q000821:virology*; D017735:Virus Latency / Q000502:physiology*; D000093322:Lymphocyte Activation Gene 3 Protein
chemical_list: D044966:Anti-Retroviral Agents; D015703:Antigens, CD; D015415:Biomarkers; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D011971:Receptors, Immunologic; C534712:TIGIT protein, human; D000093322:Lymphocyte Activation Gene 3 Protein