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

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 NF B, we unexpectedly failed to correlate Nef-induced signaling events with enhanced NF B 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 NF B-independent, pathway. The Journal of Immunology, 2008, 181: 8425–8432.