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Dengue Virus (DV) Replication in Monocyte-Derived Macrophages Is Not Affected by Tumor Necrosis Factor Alpha (TNF-), and DV Infection Induces Altered Responsiveness to TNF- Stimulation

School of Molecular and Biomedical Science, University of Adelaide, Adelaide, SA 5005, Australia, and Infectious Diseases Laboratories, Institute of Medical and Veterinary Science, Adelaide, SA 5000, Australia

Received 12 February 2007/ Accepted 27 June 2007

Tumor necrosis factor alpha (TNF-) is believed to play a significant role in the pathogenesis of dengue virus (DV) infection, with elevated levels of TNF- in the sera of DV-infected patients paralleling the severity of disease and TNF- release being coincident with the peak of DV production from infected monocyte-derived macrophages (MDM) in vitro. Since macrophages are a primary cell target in vivo for DV infection, we investigated the potential antiviral role of TNF- in regulating DV replication in MDM. While pretreatment of MDM with TNF- had a minor inhibitory effect, addition of TNF- to MDM with established DV infection had no effect on DV replication as measured by DV RNA levels or progeny virus production. Blocking endogenous TNF- using short interfering RNA or inhibitory TNF- antibodies also had no effect on infectious DV production or viral RNA synthesis. Together, these results demonstrate that DV replication in MDM is not affected by TNF-. Additionally, normal cellular TNF- signaling, measured by quantitation of TNF--induced stimulation of transcription from an NF-B-responsive reporter plasmid or NF-B protein nuclear translocation, was blocked in DV-infected MDM and Huh7 cells. Thus, DV replication in MDM is not affected by TNF-, and infected cells do not respond normally to TNF- stimulation. It is therefore unlikely that the increased production of TNF- seen in DV infection directly effects DV clearance by reducing DV replication, and the ability of DV to alter TNF- responsiveness highlights another example of viral subversion of cellular functions.

Published ahead of print on 11 July 2007.