PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression.
Functional impairment of T cells is characteristic of many chronic mouse and human viral infections. The inhibitory receptor programmed death 1 (PD-1; also known as PDCD1), a negative regulator of activated T cells, is markedly upregulated on the surface of exhausted virus-specific CD8 T cells in mice. Blockade of this pathway using antibodies against the PD ligand 1 (PD-L1, also known as CD274) restores CD8 T-cell function and reduces viral load. To investigate the role of PD-1 in a chronic human viral infection, we examined PD-1 expression on human immunodeficiency virus (HIV)-specific CD8 T cells in 71 clade-C-infected people who were naive to anti-HIV treatments, using ten major histocompatibility complex (MHC) class I tetramers specific for frequently targeted epitopes. Here we report that PD-1 is significantly upregulated on these cells, and expression correlates with impaired HIV-specific CD8 T-cell function as well as predictors of disease progression: positively with plasma viral load and inversely with CD4 T-cell count. PD-1 expression on CD4 T cells likewise showed a positive correlation with viral load and an inverse correlation with CD4 T-cell count, and blockade of the pathway augmented HIV-specific CD4 and CD8 T-cell function. These data indicate that the immunoregulatory PD-1/PD-L1 pathway is operative during a persistent viral infection in humans, and define a reversible defect in HIV-specific T-cell function. Moreover, this pathway of reversible T-cell impairment provides a potential target for enhancing the function of exhausted T cells in chronic HIV infection.
Day
Cheryl L
CL
HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu Natal, Durban 4013, South Africa.
Kaufmann
Daniel E
DE
Kiepiela
Photini
P
Brown
Julia A
JA
Moodley
Eshia S
ES
Reddy
Sharon
S
Mackey
Elizabeth W
EW
Miller
Joseph D
JD
Leslie
Alasdair J
AJ
DePierres
Chantal
C
Mncube
Zenele
Z
Duraiswamy
Jaikumar
J
Zhu
Baogong
B
Eichbaum
Quentin
Q
Altfeld
Marcus
M
Wherry
E John
EJ
Coovadia
Hoosen M
HM
Goulder
Philip J R
PJ
Klenerman
Paul
P
Ahmed
Rafi
R
Freeman
Gordon J
GJ
Walker
Bruce D
BD
D015703:Antigens, CD / Q000378:metabolism*; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology* / Q000821:virology*; D018450:Disease Progression; D015870:Gene Expression; D006678:HIV / Q000502:physiology*; D015658:HIV Infections / Q000276:immunology / Q000378:metabolism* / Q000473:pathology* / Q000821:virology; D015395:Histocompatibility Antigens Class I / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D061026:Programmed Cell Death 1 Receptor; D015854:Up-Regulation
D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; D015395:Histocompatibility Antigens Class I; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D007371:Interferon-gamma