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Journal of Virology, November 2009, p. 11528-11539, Vol. 83, No. 22
0022-538X/09/$08.00+0     doi:10.1128/JVI.01423-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Inhibition of T-Cell Receptor-Induced Actin Remodeling and Relocalization of Lck Are Evolutionarily Conserved Activities of Lentiviral Nef Proteins{triangledown}

Jochen M. Rudolph,1 Nina Eickel,2 Claudia Haller,1 Michael Schindler,2 and Oliver T. Fackler1*

Department of Virology, University of Heidelberg, INF 324, 69120 Heidelberg, Germany,1 Heinrich-Pette-Institute, 20251 Hamburg, Germany2

Received 10 July 2009/ Accepted 26 August 2009

Nef, an important pathogenicity factor of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV), elevates virus replication in vivo. Among other activities, Nef affects T-cell receptor (TCR) signaling via several mechanisms. For HIV-1 Nef these include alteration of the organization and function of the immunological synapse (IS) such as relocalization of the Lck kinase, as well as early inhibition of TCR/CD3 complex (TCR-CD3)-mediated actin rearrangements and tyrosine phosphorylation. Although most SIV and HIV-2 Nef alleles (group 2) potently downregulate cell surface TCR-CD3, this activity was lost in the viral lineage that gave rise to HIV-1 and its SIV counterparts (group 1). To address the contribution of TCR-CD3 downregulation to Nef effects on TCR signal initiation, we compared the activities of 18 group 1 and group 2 Nef proteins, as well as SIV Nef mutants with defects in TCR-CD3 downmodulation. We found that alteration of Lck's subcellular localization is largely conserved and occurs independently of actin remodeling inhibition or TCR-CD3 downregulation. Surprisingly, Nef proteins of both groups also strongly reduced TCR-induced actin remodeling and tyrosine phosphorylation on TCR-stimulatory surfaces and TCR-CD3 downmodulation competence by group 2 Nef proteins only slightly elevated these effects. Furthermore, Nef proteins from HIV-1 and SIV reduced conjugation between infected primary human T lymphocytes and Raji B cells and potently prevented F-actin polarization at the IS independently of their ability to downmodulate TCR-CD3. These results establish alterations of early TCR signaling events at the IS, including F-actin remodeling and relocalization of Lck, as evolutionary conserved activities of highly divergent lentiviral Nef proteins.

* Corresponding author. Mailing address: Department of Virology, University of Heidelberg, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany. Phone: 49-6221-561322. Fax: 49-6221-565003. E-mail: oliver.fackler{at}med.uni-heidelberg.de

{triangledown} Published ahead of print on 2 September 2009.

Journal of Virology, November 2009, p. 11528-11539, Vol. 83, No. 22
0022-538X/09/$08.00+0     doi:10.1128/JVI.01423-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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