Many viruses, including HIV1, HTLV1, HBV, HCV, EBV and Influenza virus activate NF-κB. The activation of NF-κB promotes viral replication, prevents virus-induced apoptosis, and mediates the immune response to the invading pathogen. NF-κB is normally found in the cytoplasm complexed with an inhibitory protein, I-κB. Upon infection, signaling events are initiated leading to activation of MEKK1, which is capable of phosphorylating I-κB. NF-κB then dissociates from phosphorylated I-κB and migrates to the nucleus where it activates transcription.NF-κB is constitutively activated in primary monocytes and myeloid cell lines chronically infected with HIV1. HIV1 infects CD4 T-lymphocytes through recognition of the CD4 receptor and coreceptors CXCR4/5. This induces activation of ERK1/2, JNK, AP-1 and NF-κB. Ras is also activated by CD4 cross-linking and activates NF-κB. Binding of HIV1 to CD4 also activates PI3K, which functions upstream of Akt1 to stimulate IKK. CD4 signaling upon HIV1 binding or GP120 ligation may activate NF-κB via two different but closely related pathways: 1)Through Lck and c-Raf, and 2) Through PI3K, Akt1, and IKK. Activation of NF-κB by Tat proceeds via IKK, which is constitutively active in HIV-infected cells. The ability of Tat to activate NF-κB also requires PKR.
NF-κB activation by EBV involves the interaction of GP350 with its cellular receptor CD21, which induces rapid activation of NF-κB as well as activation of PKC and PI3K. At later stages of infection, LMP1 is produced and inserted in the cellular membrane.
The expression of a single viral protein E3/19K of adenovirus is sufficient to activate NF-κB. The inducing signal is triggered by the accumulation of proteins in the ER membrane, which causes Ca2+ release from the ER.
CMV stimulates a large number of proinflammatory signaling events, including nuclear translocation of NF-κB through Glycoprotein GB. The early cellular response to human CMV infection is production of IP3 and DAG. The subsequent calcium influx and PKC activation is involved in early activation of transcription factors, including NF-κB. The mechanism of activation of NF-κB by CMV involves the liberation of the transcription factor from the inhibitory subunit IκB-α but not IκB-β. The early activation of NF-κB is amplified by other mechanisms later during infection.
The HSV genome encodes at least 11 GPs, which alone or in concert play different roles in viral adsorption, entry, cell-to-cell spreading, and immune evasion. Glycoprotein-D (GD) is essential for viral entry, which is dependent on the interaction of GD with a cellular entry mediator. At present, three entry mediators have been identified, termed HveA, HveB, and HveC, and of these at least the TNF receptor family member HveA is known to be a signaling receptor. HSV infection triggers at least two cellular signaling pathways: 1) A UV-insensitive pathway that is dependent on GD, and 2) A UV-sensitive pathway that is dependent on a functional viral genome. HSV uses HveA as receptor and HveA signaling leads to activation of NF-κB and AP-1. During later stages of infection, UV-sensitive signaling is initiated, leading to a strong activation of NF-κB and AP-1. The mechanism of sustained NF-κB activation by HSV is dependent on viral entry and immediate-early gene expression.
The cellular signaling induced by Influenza virus infection results in activation of the p38 MAPK and JNK and the downstream transcription factors NF-κB and AP-1. In addition to viral proteins, the infected cell can also detect influenza virus dsRNA. The Influenza dsRNA initiates signaling events through a mechanism dependent on the dsRNA-activated PKR.