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Analysis of the Signal Transduction Pathway Leading to Human Immunodeficiency Virus‐1‐Induced Interferon Regulatory Factor‐1 Upregulation
Author(s) -
SGARBANTI MARCO,
MARSILI GIULIA,
REMOLI ANNA LISA,
RIDOLFI BARBARA,
STELLACCI EMILIA,
BORSETTI ALESSANDRA,
ENSOLI BARBARA,
BATTISTINI ANGELA
Publication year - 2004
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1196/annals.1329.024
Subject(s) - interferon regulatory factors , biology , transcription factor , repressor , irf1 , signal transduction , response element , jurkat cells , stat1 , hiv long terminal repeat , interferon , promoter , stat protein , microbiology and biotechnology , transcription (linguistics) , long terminal repeat , gene , virology , gene expression , stat3 , genetics , immune system , t cell , linguistics , philosophy
A bstract : 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‐α/β 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‐γ‐activated sequences that bind members of the signal transducer and activator of transcription (STAT) family and binding sites for nuclear factor κB (NF‐κB). Both STAT‐1 and NF‐κB 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‐κB 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‐κB super‐repressor (IκB‐α 2NΔ4). These results suggest that in early phases of HIV‐1 infection, before detectable cytokine production, NF‐κB seems responsible for HIV‐1‐induced IRF‐1 expression.