title: HIV-mediated phosphatidylinositol 3-kinase/serine-threonine kinase activation in APCs leads to programmed death-1 ligand upregulation and suppression of HIV-specific CD8 T cells.
abstract: Recent evidence demonstrates that HIV-1 infection leads to the attenuation of cellular immune responses, which has been correlated with the increased expression of programmed death (PD)-1 on virus-specific CD8(+) T cells. PD-1 is induced upon T cell activation, and its prolonged expression facilitates CD8(+) T cell inhibitory signals when bound to its B7 family ligands, PD-ligand (L)1/2, which are expressed on APCs. Importantly, early reports demonstrated that blockade of the PD-1/PD-L interaction by Abs may help to counter the development of immune exhaustion driven by HIV viral persistence. To better understand the regulation of the PD-1 pathway during HIV infection, we examined the ability of the virus to induce PD-L expression on macrophages and dendritic cells. We found a direct relationship between the infection of APCs and the expression of PD-L1 in which virus-mediated upregulation induced a state of nonresponsiveness in uninfected HIV-specific T cells. Furthermore, this exhaustion phenotype was revitalized by the blockade of PD-L1, after which T cells regained their capacity for proliferation and the secretion of proinflammatory cytokines IFN-γ, IL-2, and IL-12 upon restimulation. In addition, we identify a critical role for the PI3K/serine-threonine kinase signaling pathway in PD-L1 upregulation of APCs by HIV, because inhibition of these intracellular signal transducer enzymes significantly reduced PD-L1 induction by infection. These data identify a novel mechanism by which HIV exploits the immunosuppressive PD-1 pathway and suggest a new role for virus-infected cells in the local corruption of immune responses required for viral suppression.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. muthuman@mail.med.upenn.edu
authors.forename: Karuppiah
authors.initials: K
authors.lastname: Muthumani
authors.forename: Devon J
authors.initials: DJ
authors.lastname: Shedlock
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Choo
authors.forename: Paolo
authors.initials: P
authors.lastname: Fagone
authors.forename: Omkar U
authors.initials: OU
authors.lastname: Kawalekar
authors.forename: Jonathan
authors.initials: J
authors.lastname: Goodman
authors.forename: Chaoran B
authors.initials: CB
authors.lastname: Bian
authors.forename: Aarti A
authors.initials: AA
authors.lastname: Ramanathan
authors.forename: Parikh
authors.initials: P
authors.lastname: Atman
authors.forename: Pablo
authors.initials: P
authors.lastname: Tebas
authors.forename: Michael A
authors.initials: MA
authors.lastname: Chattergoon
authors.forename: Andrew Y
authors.initials: AY
authors.lastname: Choo
authors.forename: David B
authors.initials: DB
authors.lastname: Weiner
mesh_terms: D000938:Antigen-Presenting Cells / Q000276:immunology* / Q000378:metabolism; D015703:Antigens, CD / Q000096:biosynthesis / Q000276:immunology; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis / Q000276:immunology; D015153:Blotting, Western; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002469:Cell Separation; D004789:Enzyme Activation / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D015658:HIV Infections / Q000276:immunology* / Q000378:metabolism; D015497:HIV-1 / Q000276:immunology; D006801:Humans; D008024:Ligands; D008213:Lymphocyte Activation / Q000276:immunology*; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology / Q000378:metabolism; D061026:Programmed Cell Death 1 Receptor; D017346:Protein Serine-Threonine Kinases / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D015854:Up-Regulation
chemical_list: D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; D008024:Ligands; D019869:Phosphatidylinositol 3-Kinases; D061026:Programmed Cell Death 1 Receptor; D017346:Protein Serine-Threonine Kinases; C105992:PDCD1 protein, human