Human immunodeficiency virus type 1 Nef induces programmed death 1 expression through a p38 mitogen-activated protein kinase-dependent mechanism.
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.
Muthumani
Karuppiah
K
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. muthuman@mail.med.upenn.edu
Choo
Andrew Y
AY
Shedlock
Devon J
DJ
Laddy
Dominick J
DJ
Sundaram
Senthil G
SG
Hirao
Lauren
L
Wu
Ling
L
Thieu
Khanh P
KP
Chung
Christopher W
CW
Lankaraman
Karthikbabu M
KM
Tebas
Pablo
P
Silvestri
Guido
G
Weiner
David B
DB
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*
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
J Virol. 2001 Mar;75(6):2993-3000
11222724
Nature. 2006 Feb 9;439(7077):682-7
16382236
Science. 1995 Nov 10;270(5238):988-91
7481804
J Immunol. 2007 Aug 1;179(3):1979-87
17641065
J Virol. 1998 Aug;72(8):6520-6
9658095
J Pharmacol Exp Ther. 1999 Nov;291(2):680-7
10525088
J Virol. 2007 Jun;81(11):5819-28
17376899
Nature. 2003 Jul 10;424(6945):213-9
12853962
J Clin Invest. 2005 Feb;115(2):443-50
15668739
Eur J Immunol. 2008 May;38(5):1435-45
18389475
Nat Immunol. 2007 Nov;8(11):1246-54
17906628
J Virol. 2007 Mar;81(6):2545-53
17182670
J Virol. 1995 Nov;69(11):6705-11
7474080
Nat Cell Biol. 2006 Feb;8(2):170-9
16429131
Annu Rev Immunol. 2008;26:677-704
18173375
J Exp Med. 2000 Oct 2;192(7):1027-34
11015443
J Exp Med. 2006 Oct 2;203(10):2223-7
17000870
N Engl J Med. 1995 Jan 26;332(4):228-32
7808489
Immunity. 1999 Aug;11(2):141-51
10485649
Nature. 1998 Jan 22;391(6665):397-401
9450757
J Exp Med. 2006 Oct 2;203(10):2281-92
16954372
J Virol. 2007 Apr;81(8):4215-25
17287266
FEBS Lett. 1996 Sep 9;393(1):93-6
8804432
J Virol. 2000 Feb;74(4):2038-45
10644378
Cell. 1998 Oct 16;95(2):163-75
9790524
Nature. 2006 Sep 21;443(7109):350-4
16921384
Nat Med. 2006 Oct;12(10):1198-202
16917489
FEBS Lett. 1999 May 21;451(2):191-6
10371163
Blood. 2005 Sep 15;106(6):2059-68
15928037
Microbiol Mol Biol Rev. 2006 Jun;70(2):548-63
16760313
Cell. 1991 May 17;65(4):651-62
2032289
EMBO J. 1995 Feb 1;14(3):484-91
7859737
Nat Immunol. 2001 Mar;2(3):261-8
11224527