Hydroxychloroquine-inhibited dengue virus is associated with host defense machinery

J Interferon Cytokine Res. 2015 Mar;35(3):143-56. doi: 10.1089/jir.2014.0038. Epub 2014 Oct 16.

Abstract

Hydroxychloroquine (HCQ) is an antimalarial drug also used in treating autoimmune diseases. Its antiviral activity was demonstrated in restricting HIV infection in vitro; however, the clinical implications remain controversial. Infection with dengue virus (DENV) is a global public health problem, and we lack an antiviral drug for DENV. Here, we evaluated the anti-DENV potential of treatment with HCQ. Immunofluorescence assays demonstrated that HCQ could inhibit DENV serotype 1-4 infection in vitro. RT-qPCR analysis of HCQ-treated cells showed induced expression of interferon (IFN)-related antiviral proteins and certain inflammatory cytokines. Mechanistic study suggested that HCQ activated the innate immune signaling pathways of IFN-β, AP-1, and NFκB. Knocking down mitochondrial antiviral signaling protein (MAVS), inhibiting TANK binding kinase 1 (TBK1)/inhibitor-κB kinase ɛ (IKKɛ), and blocking type I IFN receptor reduced the efficiency of HCQ against DENV-2 infection. Furthermore, HCQ significantly induced cellular production of reactive oxygen species (ROS), which was involved in the host defense system. Suppression of ROS production attenuated the innate immune activation and anti-DENV-2 effect of HCQ. In summary, HCQ triggers the host defense machinery by inducing ROS- and MAVS-mediated innate immune activation against DENV infection and may be a candidate drug for DENV infection.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Cell Line
  • Dengue / drug therapy*
  • Dengue Virus / immunology*
  • Epithelial Cells / drug effects*
  • Epithelial Cells / immunology
  • Epithelial Cells / virology
  • Gene Expression Regulation, Viral / drug effects
  • Humans
  • Hydroxychloroquine / pharmacology*
  • Immunity, Innate / drug effects
  • Interferons / genetics
  • Interferons / metabolism*
  • Mice
  • NF-kappa B / metabolism
  • Reactive Oxygen Species / metabolism
  • Signal Transduction / drug effects

Substances

  • Adaptor Proteins, Signal Transducing
  • NF-kappa B
  • Reactive Oxygen Species
  • VISA protein, human
  • Hydroxychloroquine
  • Interferons