Programmed death 1 expression on HIV-specific CD4+ T cells is driven by viral replication and associated with T cell dysfunction

Michelle D'Souza; Andrew P Fontenot; Doug G Mack; Catherine Lozupone; Stephanie Dillon; Amie Meditz; Cara C Wilson; Elizabeth Connick; Brent E Palmer

doi:10.4049/jimmunol.179.3.1979

Programmed death 1 expression on HIV-specific CD4+ T cells is driven by viral replication and associated with T cell dysfunction

J Immunol. 2007 Aug 1;179(3):1979-87. doi: 10.4049/jimmunol.179.3.1979.

Authors

Michelle D'Souza¹, Andrew P Fontenot, Doug G Mack, Catherine Lozupone, Stephanie Dillon, Amie Meditz, Cara C Wilson, Elizabeth Connick, Brent E Palmer

Affiliation

¹ Department of Medicine, University of Colorado at Denver and Health Sciences Center, Denver, CO 80262, USA.

PMID: 17641065
DOI: 10.4049/jimmunol.179.3.1979

Abstract

Functional impairment of HIV-specific CD4(+) T cells during chronic HIV infection is closely linked to viral replication and thought to be due to T cell exhaustion. Programmed death 1 (PD-1) has been linked to T cell dysfunction in chronic viral infections, and blockade of the PD-1 pathway restores HIV-specific CD4(+) and CD8(+) T cell function in HIV infection. This study extends those findings by directly examining PD-1 expression on virus-specific CD4(+) T cells. To investigate the role of PD-1 in HIV-associated CD4(+) T cell dysfunction, we measured PD-1 expression on blood and lymph node T cells from HIV-infected subjects with chronic disease. PD-1 expression was significantly higher on IFN-gamma-producing HIV-specific CD4(+) T cells compared with total or CMV-specific CD4(+) T cells in untreated HIV-infected subjects (p = 0.0001 and p < 0.0001, respectively). PD-1 expression on HIV-specific CD4(+) T cells from subjects receiving antiretroviral therapy was significantly reduced (p = 0.007), and there was a direct correlation between PD-1 expression on HIV-specific CD4(+) T cells and plasma viral load (r = 0.71; p = 0.005). PD-1 expression was significantly higher on HIV-specific T cells in the lymph node, the main site of HIV replication, compared with those in the blood (p = 0.0078). Thus, PD-1 expression on HIV-specific CD4(+) T cells is driven by persistent HIV replication, providing a potential target for enhancing the functional capacity of HIV-specific CD4(+) T cells.

Publication types

Comparative Study
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Antibodies, Blocking / physiology
Antigens, CD / biosynthesis*
Antigens, CD / blood
Antigens, CD / immunology
Antigens, CD / metabolism
Apoptosis Regulatory Proteins / antagonists & inhibitors
Apoptosis Regulatory Proteins / biosynthesis*
Apoptosis Regulatory Proteins / blood
Apoptosis Regulatory Proteins / metabolism
B7-H1 Antigen
Biomarkers
CD4-Positive T-Lymphocytes / immunology
CD4-Positive T-Lymphocytes / metabolism
CD4-Positive T-Lymphocytes / pathology*
CD4-Positive T-Lymphocytes / virology*
CD8-Positive T-Lymphocytes / immunology
CD8-Positive T-Lymphocytes / metabolism
CD8-Positive T-Lymphocytes / virology
Cell Proliferation
Chronic Disease
Epitopes, T-Lymphocyte / immunology
Gene Products, gag / immunology
HIV / immunology*
HIV Infections / immunology
HIV Infections / pathology
HIV Infections / virology
Humans
Immunophenotyping
Interferon-gamma / biosynthesis
Ligands
Lymph Nodes / immunology
Lymph Nodes / metabolism
Lymph Nodes / pathology
Programmed Cell Death 1 Receptor
Signal Transduction / immunology
T-Lymphocyte Subsets / immunology
T-Lymphocyte Subsets / metabolism
T-Lymphocyte Subsets / pathology
Up-Regulation / immunology
Viral Load
Virus Replication / immunology*

Substances

Antibodies, Blocking
Antigens, CD
Apoptosis Regulatory Proteins
B7-H1 Antigen
Biomarkers
CD274 protein, human
Epitopes, T-Lymphocyte
Gene Products, gag
Ligands
PDCD1 protein, human
Programmed Cell Death 1 Receptor
Interferon-gamma