title: Human immunodeficiency virus type 1 Nef induces programmed death 1 expression through a p38 mitogen-activated protein kinase-dependent mechanism.
abstract: Chronic viral infection is characterized by the functional impairment of virus-specific T-cell responses. Recent evidence has suggested that the inhibitory receptor programmed death 1 (PD-1) is specifically upregulated on antigen-specific T cells during various chronic viral infections. Indeed, it has been reported that human immunodeficiency virus (HIV)-specific T cells express elevated levels of PD-1 and that this expression correlates with the viral load and inversely with CD4(+) T-cell counts. More importantly, antibody blockade of the PD-1/PD-L1 pathway was sufficient to both increase and stimulate virus-specific T-cell proliferation and cytokine production. However, the mechanisms that mediate HIV-induced PD-1 upregulation are not known. Here, we provide evidence that the HIV type 1 (HIV-1) accessory protein Nef can transcriptionally induce the expression of PD-1 during infection in vitro. Nef-induced PD-1 upregulation requires its proline-rich motif and the activation of the downstream kinase p38. Further, inhibition of Nef activity by p38 MAPK inhibitor effectively blocked PD-1 upregulation, suggesting that p38 MAPK activation is an important initiating event in Nef-mediated PD-1 expression in HIV-1-infected cells. These data demonstrate an important signaling event of Nef in HIV-1 pathogenesis.
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: Andrew Y
authors.initials: AY
authors.lastname: Choo
authors.forename: Devon J
authors.initials: DJ
authors.lastname: Shedlock
authors.forename: Dominick J
authors.initials: DJ
authors.lastname: Laddy
authors.forename: Senthil G
authors.initials: SG
authors.lastname: Sundaram
authors.forename: Lauren
authors.initials: L
authors.lastname: Hirao
authors.forename: Ling
authors.initials: L
authors.lastname: Wu
authors.forename: Khanh P
authors.initials: KP
authors.lastname: Thieu
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Chung
authors.forename: Karthikbabu M
authors.initials: KM
authors.lastname: Lankaraman
authors.forename: Pablo
authors.initials: P
authors.lastname: Tebas
authors.forename: Guido
authors.initials: G
authors.lastname: Silvestri
authors.forename: David B
authors.initials: DB
authors.lastname: Weiner
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000378:metabolism; D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis / Q000235:genetics*; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D006801:Humans; D061026:Programmed Cell Death 1 Receptor; D015854:Up-Regulation; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology*
chemical_list: D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D054311:nef Gene Products, Human Immunodeficiency Virus; C514837:nef protein, Human immunodeficiency virus 1; D048051:p38 Mitogen-Activated Protein Kinases
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