Abstract
As a result of its interaction with transcription factors, HIV type 1 (HIV-1) Tat can modulate the expression of both HIV and cellular genes. In antigen-presenting cells Tat induces the expression of a subset of interferon (IFN)-stimulated genes (ISGs) in the absence of IFNs. We investigated the genome-wide Tat association with promoters in immature dendritic cells and in monocyte-derived macrophages. Among others, Tat associated with the MAP2K6, MAP2K3, and IRF7 promoters that are functionally part of IL-1 and p38 mitogen-activated protein kinase (MAPK) signaling pathways. The association correlated with their increased gene expression, increased activation of p38 MAPK and of phosphorylated signal transducer and activator of transcription 1 (STAT1), and consequent induction of ISGs. Probing these pathways with RNA interference, pharmacological p38 MAPK inhibition, and in cell lines lacking STAT1s or the type I IFN receptor chain confirmed the role of MAPKKs and IRF7 in Tat-mediated modulation of ISGs and excluded the involvement of IFNs in this modulation. Tat interaction with the 2 MAPKK and IRF7 promoters in HIV-1-infected cells and the resulting persistent activation of ISGs, which include inflammatory cytokines and chemokines, can contribute to the increased immune activation that characterizes HIV infection.
Publication types
-
Research Support, N.I.H., Extramural
MeSH terms
-
Antigen-Presenting Cells / immunology
-
Antigen-Presenting Cells / metabolism*
-
Antigen-Presenting Cells / physiology
-
Cells, Cultured
-
Chemokines / genetics
-
Chemokines / metabolism
-
Gene Products, tat / metabolism*
-
Gene Products, tat / physiology
-
HIV Infections / genetics
-
HIV Infections / immunology
-
HIV-1 / physiology
-
Humans
-
Interferon Regulatory Factor-7 / genetics*
-
Interferon Regulatory Factor-7 / metabolism
-
Interferon Regulatory Factor-7 / physiology
-
Interferons / pharmacology*
-
Lymphocyte Activation / drug effects
-
Lymphocyte Activation / genetics
-
MAP Kinase Kinase 3 / genetics*
-
MAP Kinase Kinase 3 / metabolism
-
MAP Kinase Kinase 6 / genetics*
-
MAP Kinase Kinase 6 / metabolism
-
Promoter Regions, Genetic*
-
Protein Binding
-
Receptors, Chemokine / genetics
-
Receptors, Chemokine / metabolism
-
Signal Transduction / genetics
-
Signal Transduction / physiology
-
Up-Regulation / drug effects
-
Up-Regulation / genetics
-
p38 Mitogen-Activated Protein Kinases / genetics
-
p38 Mitogen-Activated Protein Kinases / metabolism*
-
p38 Mitogen-Activated Protein Kinases / physiology
Substances
-
Chemokines
-
Gene Products, tat
-
IRF7 protein, human
-
Interferon Regulatory Factor-7
-
Receptors, Chemokine
-
Interferons
-
p38 Mitogen-Activated Protein Kinases
-
MAP Kinase Kinase 3
-
MAP Kinase Kinase 6
-
MAP2K3 protein, human
-
MAP2K6 protein, human