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Induction of HIV Transcription by Nef Involves Lck Activation and Protein Kinase C Raft Recruitment Leading to Activation of ERK1/2 but Not NFB¹

Vanessa Witte^2,*, Bernd Laffert^3,, Patricia Gintschel^*, Ellen Krautkrämer, Katja Blume, Oliver T. Fackler and Andreas S. Baur^4,

^* Otto-von-Guericke University of Magdeburg, Institute of Molecular and Clinical Immunology, Leipziger Str. 44, Magdeburg, Germany; University of Miami, Miller School of Medicine, Department of Microbiology and Immunology, Miami, FL 33136; Friedrich-Alexander University of Erlangen, Department of Dermatology, Hartmannstr. 14, Erlangen, Germany; and University of Heidelberg, Department of Virology, Im Neuenheimer Feld 324, Heidelberg, Germany

The Nef protein of HIV-1 is a key promoter of disease progression, owing to its dramatic yet ill-defined impact on viral replication. Previously, we have shown that Nef enhances embryonic ectodermal development Tat-mediated transcription in a manner depending on Lck and the cytoplasmic sequestration of the transcriptional repressor embryonic ectodermal development. In this study, we report that Lck is activated by Nef and targets protein kinase C downstream, leading to the translocation of the kinase into membrane microdomains. Although microdomain-localized protein kinase C is thought to induce the transcription factor NFB, we unexpectedly failed to correlate Nef-induced signaling events with enhanced NFB activity. Instead, we observed an increase in ERK MAPK activity. We conclude that Nef-mediated signaling cooperates with Nef-induced derepression and supports HIV transcription through an ERK MAPK-dependent, but NFB-independent, pathway.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by funds from the Department of Microbiology and Immunology, University of Miami, Miller School of Medicine (grants to A.S.B.) and the Deutsche Forschungsgemeinschaft (Grant TR7013 to O.T.F.).

² Address correspondence and reprint requests to Dr. Vanessa Witte, Otto-von-Guericke University of Magdeburg, Institute of Molecular and Clinical Immunology, Leipziger Str. 44, 39120 Magdeburg, Germany. E-mail address: vanessa.witte{at}med.ovgu.de

³ Current address: CCS Cell Culture Service GmbH, Falkenried 88, 20251 Hamburg, Germany.

⁴ Current address: Friedrich-Alexander University of Erlangen, Department of Dermatology, Hartmannstr. 14, 91052 Erlangen, Germany.

⁵ Abbreviations used in this paper: NAKC, Nef-associated kinase complex; EED, embryonic ectodermal development; PKC, protein kinase C; DRM, detergent-resistant membrane; MβCD, methyl-β-cyclodextrin.

⁶ The online version of this article contains supplementary material.