HIV-1 blocks the signaling adaptor MAVS to evade antiviral host defense after sensing of abortive HIV-1 RNA by the host helicase DDX3

Gringhuis SI et al., Nat Immunol 2017, 18(2): 225-235.

Speaker: Wei-Ren Cheng (鄭惟仁)                                      Time: 14:10~15:00, Mar 1, 2017

Commentator: Dr. Shainn-Wei Wang (王憲威 老師) Place: Room 601

Abstract:

Dendritic cells (DCs) detect invading viruses to trigger type I interferon responses against viral infection. However, type I interferon responses is not induced in HIV-infected DCs (1). The issue whether the signaling utilized by HIV leads to the inhibition of type I interferon in DCs remains unclear. Previous studies showed that HIV uses DC-SIGN-HIV interaction induced Raf-1 signaling for viral RNA elongation, and eventually leads to productive infection in DCs (2). Therefore, the author blocked Raf-1 signaling by siRNA and a specific inhibitor GW5074 and found that Raf-1 signaling is required for the inhibition of HIV transcripts induced-type I interferon responses during HIV infection. They further identified DDX3, a RNA helicase that assists nuclear export of HIV transcripts, as RNA sensor of abortive HIV RNA and activated type I interferon responses through MAVS-TRAF3 signaling pathways. To clarify the mechanism of Raf-1 signaling in the inhibition of DDX3-MAVS-TRAF3 signaling pathways, they targeted PLK1, a kinase that can interact with MAVS and block MAVS-TRAF3 interaction. Results showed that Raf-1 signaling induces the association of PLK1 with MAVS and leads to the inhibition of DDX3-MAVS-TRAF3 signaling pathways. They also identified MAVS mutation, which prevents PLK1-mediated MAVS suppression and resists to HIV-infection in humans. Taken together, HIV-DC-SIGN interaction-mediated PLK1 activation can inhibit DDX3-MAVS-TRAF3 signaling pathways and further block IFN-I responses in HIV-infected DCs. This finding provides a new strategy to block HIV infection by targeting Raf-1 signaling.

References:

1.     Miller E, Bhardwaj N. Dendritic cell dysregulation during HIV-1 infection. Immunological reviews 2013, 254(1): 170-189.

2.     Gringhuis SI, van der Vlist M, van den Berg LM, den Dunnen J, Litjens M, Geijtenbeek TBH. HIV-1 exploits innate signaling by TLR8 and DC-SIGN for productive infection of dendritic cells. Nat Immunol 2010, 11(5): 419-426.