title: Decreased 4-1BB expression on HIV-specific CD4+ T cells is associated with sustained viral replication and reduced IL-2 production.
abstract: CD4+ T cell dysfunction in subjects with chronic HIV infection is in part due to an imbalance of costimulatory and coinhibitory receptors. We report that virus-specific CD4+ T cells expressing 4-1BB (CD137) or OX40 (CD134) produced more IL-2 than cells lacking these costimulatory receptors (P<0.05) and that 4-1BB was expressed at a lower level on HIV- than CMV-specific IFN-gamma and IL-2 producing CD4+ T cells (P<0.0001 and P<0.01, respectively). Suppression of viral replication with antiretroviral therapy was associated with increased 4-1BB expression on HIV- and CMV-specific IL-2 producing CD4+ T cells (P<0.05 and P<0.01, respectively) and the percentage of IL-2 producing HIV-specific CD4+ T cells that expressed 4-1BB was inversely correlated with HIV plasma viral load (r=-0.75, P=0.007). These findings indicate that the loss of 4-1BB on HIV-specific CD4+ T cells is associated with viral replication and that it may contribute to reduced IL-2 production observed during chronic infection.
authors.affiliation: Division of Allergy and Clinical Immunology, Department of Medicine, University of Colorado Denver, Aurora, CO 80045, USA.
authors.forename: Afework
authors.initials: A
authors.lastname: Kassu
authors.forename: Michelle
authors.initials: M
authors.lastname: D'Souza
authors.forename: Brian P
authors.initials: BP
authors.lastname: O'Connor
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Kelly-McKnight
authors.forename: Ramesh
authors.initials: R
authors.lastname: Akkina
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Fontenot
authors.forename: Brent E
authors.initials: BE
authors.lastname: Palmer
mesh_terms: D053330:4-1BB Ligand / Q000096:biosynthesis; D000704:Analysis of Variance; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism / Q000821:virology; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D015658:HIV Infections / Q000097:blood / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis*; D009000:Monocytes / Q000276:immunology / Q000378:metabolism / Q000821:virology; D022423:Myeloid Cells / Q000276:immunology / Q000378:metabolism / Q000821:virology; D053278:OX40 Ligand / Q000096:biosynthesis; D053262:Receptors, OX40 / Q000096:biosynthesis*; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000096:biosynthesis*; D014779:Virus Replication
chemical_list: D053330:4-1BB Ligand; D007376:Interleukin-2; D053278:OX40 Ligand; D053262:Receptors, OX40; C505716:TNFRSF4 protein, human; C505714:TNFRSF9 protein, human; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D007371:Interferon-gamma