Journal of Interferon & Cytokine Research 2015-03-01

Hydroxychloroquine-inhibited dengue virus is associated with host defense machinery.

Li-Fong Wang, You-Sheng Lin, Nan-Chieh Huang, Chia-Yi Yu, Wei-Lun Tsai, Jih-Jung Chen, Toru Kubota, Mayumi Matsuoka, Siang-Ru Chen, Chih-Shiang Yang, Ruo-Wei Lu, Yi-Ling Lin, Tsung-Hsien Chang

Index: J. Interferon Cytokine Res. 35(3) , 143-56, (2015)

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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.