title: PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression.
abstract: 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.
authors.affiliation: HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu Natal, Durban 4013, South Africa.
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Day
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Kaufmann
authors.forename: Photini
authors.initials: P
authors.lastname: Kiepiela
authors.forename: Julia A
authors.initials: JA
authors.lastname: Brown
authors.forename: Eshia S
authors.initials: ES
authors.lastname: Moodley
authors.forename: Sharon
authors.initials: S
authors.lastname: Reddy
authors.forename: Elizabeth W
authors.initials: EW
authors.lastname: Mackey
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Miller
authors.forename: Alasdair J
authors.initials: AJ
authors.lastname: Leslie
authors.forename: Chantal
authors.initials: C
authors.lastname: DePierres
authors.forename: Zenele
authors.initials: Z
authors.lastname: Mncube
authors.forename: Jaikumar
authors.initials: J
authors.lastname: Duraiswamy
authors.forename: Baogong
authors.initials: B
authors.lastname: Zhu
authors.forename: Quentin
authors.initials: Q
authors.lastname: Eichbaum
authors.forename: Marcus
authors.initials: M
authors.lastname: Altfeld
authors.forename: E John
authors.initials: EJ
authors.lastname: Wherry
authors.forename: Hoosen M
authors.initials: HM
authors.lastname: Coovadia
authors.forename: Philip J R
authors.initials: PJ
authors.lastname: Goulder
authors.forename: Paul
authors.initials: P
authors.lastname: Klenerman
authors.forename: Rafi
authors.initials: R
authors.lastname: Ahmed
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Freeman
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Walker
mesh_terms: 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
chemical_list: 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