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

Abstract

The mechanisms by which human immunodeficiency virus 1 (HIV-1) avoids immune surveillance by dendritic cells (DCs), and thereby prevents protective adaptive immune responses, remain poorly understood. Here we showed that HIV-1 actively arrested antiviral immune responses by DCs, which contributed to efficient HIV-1 replication in infected individuals. We identified the RNA helicase DDX3 as an HIV-1 sensor that bound abortive HIV-1 RNA after HIV-1 infection and induced DC maturation and type I interferon responses via the signaling adaptor MAVS. Notably, HIV-1 recognition by the C-type lectin receptor DC-SIGN activated the mitotic kinase PLK1, which suppressed signaling downstream of MAVS, thereby interfering with intrinsic host defense during HIV-1 infection. Finally, we showed that PLK1-mediated suppression of DDX3-MAVS signaling was a viral strategy that accelerated HIV-1 replication in infected individuals.

Double-Stranded RNA Sensors and Modulators in Innate Immunity

“…However, a more recent study failed to confirm the antiviral function of DDX60 against a broad range of viruses (207), demanding more detailed studies to understand the precise role of DDX60. Additional examples of helicases reported to function in innate immune signaling in response to dsRNA include DHX15 (208), DHX33 (209,210), DHX29 (211,212), DDX3 (213,214), and the complex of DDX1-DDX21-DHX36 (215). Some helicases, such as DDX17, were shown to function as antiviral effectors independent of immune signaling pathways (16), analogous to the reported effector functions of RLRs (61) and DDX60 (206).…”

Human dendritic cell-specific ICAM-3-grabbing non-integrin downstream signaling alleviates renal fibrosis via Raf-1 activation in systemic candidiasis

“…48 HIV-1 recognition by DC-SIGN blocks type I interferon responses via Raf-1-PLK1 activation. 49 In addition, there is increasing evidence that shows the involvement of MAPKs (p38, JNK, and ERK1/2) in fibrosis. [33][34][35] ERK1/2, JNK, and p38 are activated in the obstructed kidney.…”

Diverse Roles of DEAD/DEAH-Box Helicases in Innate Immunity and Diseases

“…[47] THF cells [52] hepatitis C [54À57] HIV-1 [55,58,59] norovirus, West Nile virus, Japanese encephalitis virus [55] MAVS À DDX3 can activate MAVS and act as a scaffolding adaptor in downstream signaling TRAF3 [46] À Interaction between DDX3 and TRAF3 triggers K63-linked polyubiquitination and oligomerization of TRAF3 IKKε [45,46] À IKKε and DDX3 phosphorylate each other to promote downstream signaling in the MAVS pathway TBK1 [47] À DDX3 undergoes phosphorylation by TBK1 before it can act as a transcription factor for IFN-β PP2A [48] À Positive regulation of NF-κB transcriptional activity by modulation of PP2A activity NF-κB subunit p65 [49] À Suppression of NF-κB transcriptional activity eIF4E and PABP1 [50] À Promotion of stress granule formation and inhibition of translation Sensor of bacterial and viral RNA, activates the NLRP3 inflammasome in macrophages. [85,86].…”

“…Since DDX3 is important for the maintenance of lipid homeostasis, such decrease in expression levels and sequestration of DDX3 does not only aid in the viral evasion of the host immunity, but also results in retention of lipids in cells and subsequent steatosis [54]. Similarly, HIV-1 interrupts MAVS signaling as viral feedback to the initial sensing of HIV-1 RNA by DDX3 [58]. At the same time, HIV-1 utilizes the CRM1/ DDX3 complex in nucleus for the Rev-dependent nuclear export of viral RNAs, or DDX3 itself to promote the translation of the HIV-1 unspliced mRNA [59].…”