title: Upregulation of CTLA-4 by HIV-specific CD4+ T cells correlates with disease progression and defines a reversible immune dysfunction.
abstract: In progressive viral infection, antiviral T cell function is impaired by poorly understood mechanisms. Here we report that the inhibitory immunoregulatory receptor CTLA-4 was selectively upregulated in human immunodeficiency virus (HIV)-specific CD4(+) T cells but not CD8(+) T cells in all categories of HIV-infected subjects evaluated, with the exception of rare people able to control viremia in the absence of antiretroviral therapy. CTLA-4 expression correlated positively with disease progression and negatively with the capacity of CD4(+) T cells to produce interleukin 2 in response to viral antigen. Most HIV-specific CD4(+) T cells coexpressed CTLA-4 and another inhibitory immunoregulatory receptor, PD-1. In vitro blockade of CTLA-4 augmented HIV-specific CD4(+) T cell function. These data, indicating a reversible immunoregulatory pathway selectively associated with CD4(+) T cell dysfunction, provide a potential target for immunotherapy in HIV-infected patients.
authors: Partners AIDS Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. dkaufmann@partners.org
authors: Daniel E
authors: DE
authors: Kaufmann
authors: Daniel G
authors: DG
authors: Kavanagh
authors: Florencia
authors: F
authors: Pereyra
authors: John J
authors: JJ
authors: Zaunders
authors: Elizabeth W
authors: EW
authors: Mackey
authors: Toshiyuki
authors: T
authors: Miura
authors: Sarah
authors: S
authors: Palmer
authors: Mark
authors: M
authors: Brockman
authors: Almas
authors: A
authors: Rathod
authors: Alicja
authors: A
authors: Piechocka-Trocha
authors: Brett
authors: B
authors: Baker
authors: Baogong
authors: B
authors: Zhu
authors: Sylvie
authors: S
authors: Le Gall
authors: Michael T
authors: MT
authors: Waring
authors: Ryan
authors: R
authors: Ahern
authors: Kristin
authors: K
authors: Moss
authors: Anthony D
authors: AD
authors: Kelleher
authors: John M
authors: JM
authors: Coffin
authors: Gordon J
authors: GJ
authors: Freeman
authors: Eric S
authors: ES
authors: Rosenberg
authors: Bruce D
authors: BD
authors: Walker
mesh_terms: D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism*; D000943:Antigens, Differentiation / Q000378:metabolism*; D051017:Apoptosis Regulatory Proteins / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000821:virology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000821:virology; D060908:CTLA-4 Antigen; D016207:Cytokines / Q000378:metabolism; D018450:Disease Progression; D015658:HIV Infections / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D016133:Polymerase Chain Reaction; D061026:Programmed Cell Death 1 Receptor; D015854:Up-Regulation; D019562:Viral Load
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D051017:Apoptosis Regulatory Proteins; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D016207:Cytokines; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor