Upregulation of CTLA-4 by HIV-specific CD4+ T cells correlates with disease progression and defines a reversible immune dysfunction.
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.
Kaufmann
Daniel E
DE
Partners AIDS Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. dkaufmann@partners.org
Kavanagh
Daniel G
DG
Pereyra
Florencia
F
Zaunders
John J
JJ
Mackey
Elizabeth W
EW
Miura
Toshiyuki
T
Palmer
Sarah
S
Brockman
Mark
M
Rathod
Almas
A
Piechocka-Trocha
Alicja
A
Baker
Brett
B
Zhu
Baogong
B
Le Gall
Sylvie
S
Waring
Michael T
MT
Ahern
Ryan
R
Moss
Kristin
K
Kelleher
Anthony D
AD
Coffin
John M
JM
Freeman
Gordon J
GJ
Rosenberg
Eric S
ES
Walker
Bruce D
BD
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
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