title: Nef promotes evasion of human immunodeficiency virus type 1-infected cells from the CTLA-4-mediated inhibition of T-cell activation.
abstract: CTLA-4 is a negative regulator of T-cell receptor-mediated CD4(+) T-cell activation and function. Upregulation of CTLA-4 during human immunodeficiency virus type 1 (HIV-1) infection on activated T cells, particularly on HIV-specific CD4(+) T cells, correlates with immune dysfunction and disease progression. As HIV-1 infects and replicates in activated CD4(+) T cells, we investigated mechanisms by which HIV-1 modulates CTLA-4 expression to establish productive viral infection in these cells. Here, we demonstrate that HIV-1 infection in activated CD4(+) T cells was followed by Nef-mediated downregulation of CTLA-4. This was associated with a decreased T-cell activation threshold and significant resistance to CTLA-4 triggering. In line with these in vitro results, quantification of pro-viral HIV DNA from treatment-naive HIV-infected subjects demonstrated a preferential infection of memory CD4(+)CTLA-4(+) T cells, thus identifying CTLA-4 as a biomarker for HIV-infected cells in vivo. As transcriptionally active HIV-1 and Nef expression in vivo were previously shown to take place mainly in the CD3(+)CD4(-)CD8(-) [double-negative (DN)] cells, we further quantified HIV DNA in the CTLA-4(+) and CTLA-4(-) subpopulations of these cells. Our results showed that DN T cells lacking CTLA-4 expression were enriched in HIV DNA compared with DN CTLA-4(+) cells. Together, these results suggested that HIV-1 preferential infection of CD4(+)CTLA-4(+) T cells in vivo was followed by Nef-mediated concomitant downregulation of both CD4 and CTLA-4 upon transition to productive infection. This also highlights the propensity of HIV-1 to evade restriction of the key negative immune regulator CTLA-4 on cell activation and viral replication, and therefore contributes to the overall HIV-1 pathogenesis.
authors: Department of Microbiology, Infectiology and Immunology, Université de Montréal, Québec, Canada.|Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada.
authors: Mohamed
authors: M
authors: El-Far
authors: Department of Microbiology, Infectiology and Immunology, Université de Montréal, Québec, Canada.|Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada.
authors: Petronela
authors: P
authors: Ancuta
authors: Division of Hematology and Chronic Viral Illness Service, McGill University Health Centre, McGill University, Montréal, Québec, Canada.
authors: Jean-Pierre
authors: JP
authors: Routy
authors: Vaccine & Gene Therapy Institute Florida, Port St Lucie, FL, USA.|Department of Microbiology, Infectiology and Immunology, Université de Montréal, Québec, Canada.|Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada.
authors: Yuwei
authors: Y
authors: Zhang
authors: Vaccine & Gene Therapy Institute Florida, Port St Lucie, FL, USA.
authors: Wendy
authors: W
authors: Bakeman
authors: Vaccine & Gene Therapy Institute Florida, Port St Lucie, FL, USA.|Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada.
authors: Rebeka
authors: R
authors: Bordi
authors: Vaccine & Gene Therapy Institute Florida, Port St Lucie, FL, USA.|Department of Microbiology, Infectiology and Immunology, Université de Montréal, Québec, Canada.|Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada.
authors: Sandrina
authors: S
authors: DaFonseca
authors: Department of Microbiology, Infectiology and Immunology, Université de Montréal, Québec, Canada.|Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada.
authors: Elias A
authors: EA
authors: Said
authors: Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada.
authors: Annie
authors: A
authors: Gosselin
authors: Department of Microbiology, Infectiology and Immunology, Université de Montréal, Québec, Canada.|Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada.
authors: Tévy-Suzy
authors: TS
authors: Tep
authors: Vanderbilt University, School of Medicine, Nashville, TN, USA.
authors: Quentin
authors: Q
authors: Eichbaum
authors: Vaccine & Gene Therapy Institute Florida, Port St Lucie, FL, USA.|Department of Microbiology, Infectiology and Immunology, Université de Montréal, Québec, Canada.|Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada.
authors: Julien
authors: J
authors: van Grevenynghe
authors: Virus and Immunity Group, Department of Virology, Institut Pasteur, Paris, France.
authors: Olivier
authors: O
authors: Schwartz
authors: Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors: Gordon J
authors: GJ
authors: Freeman
authors: Vaccine & Gene Therapy Institute Florida, Port St Lucie, FL, USA.|Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada.
authors: Elias K
authors: EK
authors: Haddad
authors: Vaccine & Gene Therapy Institute Florida, Port St Lucie, FL, USA.|Department of Microbiology, Infectiology and Immunology, Université de Montréal, Québec, Canada.|Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada.
authors: Nicolas
authors: N
authors: Chomont
authors: Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada.|Case Western Reserve University, Cleveland, OH, USA.|Department of Microbiology, Infectiology and Immunology, Université de Montréal, Québec, Canada.|Vaccine & Gene Therapy Institute Florida, Port St Lucie, FL, USA.
authors: Rafick-Pierre
authors: RP
authors: Sékaly
mesh_terms: D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology*; D060908:CTLA-4 Antigen / Q000096:biosynthesis*; D005260:Female; D005786:Gene Expression Regulation; D015497:HIV-1 / Q000276:immunology / Q000502:physiology*; D054884:Host-Pathogen Interactions; D006801:Humans; D057131:Immune Evasion; D008297:Male; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*
chemical_list: D060908:CTLA-4 Antigen; D054311:nef Gene Products, Human Immunodeficiency Virus; C514837:nef protein, Human immunodeficiency virus 1
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