Exogenous Nef protein activates NF-kappa B, AP-1, and c-Jun N-terminal kinase and stimulates HIV transcription in promonocytic cells. Role in AIDS pathogenesis.
The human immunodeficiency virus (HIV) Nef protein plays a critical role in AIDS pathogenesis by enhancing replication and survival of the virus within infected cells and by facilitating its spread in vivo. Most of the data obtained so far have been in experiments with endogenous Nef protein, so far overlooking the effects of exogenous soluble Nef protein. We used recombinant exogenous Nef proteins to activate nuclear transcription factors NF-kappaB and AP-1 in the promonocytic cell line U937. Exogenous SIV and HIV-1 Nef proteins activated NF-kappaB and AP-1 in a dose- and time-dependent manner. Activation of NF-kappaB by exogenous Nef was concomitant to the degradation of the inhibitor of NF-kappaB, IkappaBalpha. In agreement with increased AP-1 activation, a time- and dose-dependent increase in JNK activation was observed following treatment of U937 cells with exogenous Nef. Since exogenous Nef activates the transcription factors NF-kappaB and AP-1, which bind to the HIV-1 long terminal repeat (LTR), we investigated the effect of exogenous Nef on HIV-1 replication. We observed that exogenous Nef stimulated HIV-1 LTR via NF-kappaB activation in U937 cells and enhanced viral replication in the chronically infected promonocytic cells U1. Therefore, our results suggest that exogenous Nef could fuel the progression of the disease via stimulation of HIV-1 provirus present in such cellular reservoirs as mononuclear phagocytes in HIV-infected patients.
Varin
Audrey
A
Department of Virology and Institut d'Etude et de Transfert de Gènes, Franche-Comté University, F-25030 Besançon, France.
Manna
Sunil K
SK
Quivy
Vincent
V
Decrion
Anne-Zélie
AZ
Van Lint
Carine
C
Herbein
Georges
G
Aggarwal
Bharat B
BB
D000163:Acquired Immunodeficiency Syndrome / Q000821:virology*; D015153:Blotting, Western; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D015693:Gene Products, nef / Q000502:physiology*; D017930:Genes, Reporter; D006678:HIV / Q000378:metabolism*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009000:Monocytes / Q000201:enzymology* / Q000821:virology; D016328:NF-kappa B / Q000378:metabolism*; D015398:Signal Transduction; D015302:Simian Immunodeficiency Virus / Q000378:metabolism; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D020298:U937 Cells; D014779:Virus Replication / Q000235:genetics; D054311:nef Gene Products, Human Immunodeficiency Virus
D015693:Gene Products, nef; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D054311:nef Gene Products, Human Immunodeficiency Virus; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases