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Journal of Virology, December 2008, p. 11536-11544, Vol. 82, No. 23
0022-538X/08/$08.00+0     doi:10.1128/JVI.00485-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Human Immunodeficiency Virus Type 1 Nef Induces Programmed Death 1 Expression through a p38 Mitogen-Activated Protein Kinase-Dependent Mechanism

Karuppiah Muthumani,^1*, Andrew Y. Choo,^2, Devon J. Shedlock,¹ Dominick J. Laddy,¹ Senthil G. Sundaram,¹ Lauren Hirao,¹ Ling Wu,¹ Khanh P. Thieu,³ Christopher W. Chung,¹ Karthikbabu M. Lankaraman,¹ Pablo Tebas,⁴ Guido Silvestri,¹ and David B. Weiner¹

Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104,¹ Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115,² Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115,³ Division of Infectious Diseases, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104⁴

Received 5 March 2008/ Accepted 3 September 2008

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.

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* Corresponding author. Mailing address: Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104. Phone: (215) 662-2352. Fax: (215) 573-9436. E-mail: muthuman{at}mail.med.upenn.edu

Published ahead of print on 17 September 2008.

K.M. and A.Y.C. contributed equally to this work.

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Journal of Virology, December 2008, p. 11536-11544, Vol. 82, No. 23
0022-538X/08/$08.00+0     doi:10.1128/JVI.00485-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

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