The Nef protein of HIV-1 associates with rafts and primes T cells for activation.
The Nef protein is an important virulence factor of primate lentiviruses, yet the mechanisms by which it exerts this influence are imperfectly understood. Here, using an inducible system, we demonstrate that Nef increases IL-2 secretion from T cells stimulated via CD3 or CD28. This effect requires the conservation of the Nef myristoylation signal and SH3-binding proline-based motif. Together with several proteins involved in the initiation and propagation of T cell signaling, Nef associates with membrane microdomains known as rafts. The Nef-mediated superinduction of IL-2 reflects the activation of both NFAT and NFkappaB. Accordingly, Nef also enhances HIV-1 transcription in response to CD3 or CD28 stimulation. Nef-induced IL-2 hyperresponsiveness is also observed in primary CD4 lymphocytes. Overall, these data suggest that Nef acts at the level of rafts to prime T cells for activation. Likely consequences of this effect are the promotion of HIV-1 replication and the facilitation of virus spread.
Wang
J K
JK
Department of Genetics and Microbiology, University of Geneva, CH-1211 Geneva, Switzerland.
Kiyokawa
E
E
Verdin
E
E
Trono
D
D
D015703:Antigens, CD / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D015967:Gene Expression Regulation, Viral / Q000276:immunology; D015693:Gene Products, nef / Q000494:pharmacology*; D017930:Genes, Reporter; D006017:Glycolipids / Q000378:metabolism; D016325:HIV Long Terminal Repeat / Q000235:genetics; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics / Q000378:metabolism; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000276:immunology*; D019814:Myristic Acid / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D014779:Virus Replication; D054311:nef Gene Products, Human Immunodeficiency Virus
D015703:Antigens, CD; D004268:DNA-Binding Proteins; D015693:Gene Products, nef; D006017:Glycolipids; D007376:Interleukin-2; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D014157:Transcription Factors; D054311:nef Gene Products, Human Immunodeficiency Virus; D019814:Myristic Acid