Analysis of the signal transduction pathway leading to human immunodeficiency virus-1-induced interferon regulatory factor-1 upregulation.
Interferon (IFN) regulatory factors (IRFs) constitute a family of transcriptional activators and repressors involved in the regulation of immune system, host defense, and cell growth. All members share conserved DNA-binding domains that recognize DNA sequences termed IRF-binding elements/IFN-stimulated response elements (IRF-E/ISRE) present on the promoter of IFN-alpha/beta and IFN-stimulated genes. An ISRE has been identified downstream of the transcription start site of the long terminal repeat (LTR) of human immunodeficiency virus-1 (HIV-1). Our previous results showed that among the IRF factors, IRF-1 is able to stimulate HIV-1 LTR transcription and its expression is induced by HIV-1, early, upon infection and before the expression of Tat. In this study we investigated the signal transduction pathway leading to HIV-1-induced IRF-1 expression. Key IRF-1 promoter elements that mediate the activation of transcription upon induction by inflammatory cytokines are IFN-gamma-activated sequences that bind members of the signal transducer and activator of transcription (STAT) family and binding sites for nuclear factor kappaB (NF-kappaB). Both STAT-1 and NF-kappaB activation were examined to determine putative molecular targets whose inhibition resulted in the inhibition of HIV-1 replication. The results show that at early time points after HIV-1 infection, NF-kappaB but not STAT-1 is activated. Moreover, a significant decrease in HIV-1 replication was observed upon de novo infection of Jurkat T cells expressing an NF-kappaB super-repressor (IkappaB-alpha 2NDelta4). These results suggest that in early phases of HIV-1 infection, before detectable cytokine production, NF-kappaB seems responsible for HIV-1-induced IRF-1 expression.
Sgarbanti
Marco
M
Department of Infectious, Parasitic, and Immunomediated Diseases, Istituto Superiore di Sanità, Viale Regina Elena, 299-00161 Rome, Italy.
Marsili
Giulia
G
Remoli
Anna Lisa
AL
Ridolfi
Barbara
B
Stellacci
Emilia
E
Borsetti
Alessandra
A
Ensoli
Barbara
B
Battistini
Angela
A
D001483:Base Sequence; D002460:Cell Line; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000502:physiology*; D024202:Electrophoretic Mobility Shift Assay; D016325:HIV Long Terminal Repeat; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D050856:Interferon Regulatory Factor-1; D010750:Phosphoproteins / Q000502:physiology*; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D015854:Up-Regulation / Q000502:physiology*; D014779:Virus Replication
D017931:DNA Primers; D004268:DNA-Binding Proteins; C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; D010750:Phosphoproteins