title: Programmed death 1 expression on HIV-specific CD4+ T cells is driven by viral replication and associated with T cell dysfunction.
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.
authors.affiliation: Department of Medicine, University of Colorado at Denver and Health Sciences Center, Denver, CO 80262, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: D'Souza
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Fontenot
authors.forename: Doug G
authors.initials: DG
authors.lastname: Mack
authors.forename: Catherine
authors.initials: C
authors.lastname: Lozupone
authors.forename: Stephanie
authors.initials: S
authors.lastname: Dillon
authors.forename: Amie
authors.initials: A
authors.lastname: Meditz
authors.forename: Cara C
authors.initials: CC
authors.lastname: Wilson
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Connick
authors.forename: Brent E
authors.initials: BE
authors.lastname: Palmer
mesh_terms: D000328:Adult; D019138:Antibodies, Blocking / Q000502:physiology; D015703:Antigens, CD / Q000096:biosynthesis* / Q000097:blood / Q000276:immunology / Q000378:metabolism; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000097:blood / Q000378:metabolism; D060890:B7-H1 Antigen; D015415:Biomarkers; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology* / Q000821:virology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000821:virology; D049109:Cell Proliferation; D002908:Chronic Disease; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D015683:Gene Products, gag / Q000276:immunology; D006678:HIV / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology / Q000473:pathology / Q000821:virology; D006801:Humans; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000096:biosynthesis; D008024:Ligands; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D061026:Programmed Cell Death 1 Receptor; D015398:Signal Transduction / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation / Q000276:immunology; D019562:Viral Load; D014779:Virus Replication / Q000276:immunology*
chemical_list: D019138:Antibodies, Blocking; D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; D060890:B7-H1 Antigen; D015415:Biomarkers; C423236:CD274 protein, human; D018984:Epitopes, T-Lymphocyte; D015683:Gene Products, gag; D008024:Ligands; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D007371:Interferon-gamma