Keap1 recognizes EIAV early accessory protein Rev to promote antiviral defense.

Yan Wang,Xue-Feng Wang,Lei Na,Xiaojun Wang,Jiaqi Zhang,Guanqin Ma,Yuezhi Lin,Xing Guo,Cong Liu,Cheng Du,Ting Qi

doi:10.1371/journal.ppat.1009986

Yan Wang, Xue-Feng Wang + Show 9 more

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https://doi.org/10.1371/journal.ppat.1009986

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Abstract

The Nrf2/Keap1 axis plays a complex role in viral susceptibility, virus-associated inflammation and immune regulation in host cells. However, whether or how the Nrf2/Keap1 axis is involved in the interactions between equine lentiviruses and their hosts remains unclear. Here, we demonstrate that the Nrf2/Keap1 axis was activated during EIAV infection. Mechanistically, EIAV-Rev competitively binds to Keap1 and releases Nrf2 from Keap1-mediated repression, leading to the accumulation of Nrf2 in the nucleus and promoting Nrf2 responsive genes transcription. Subsequently, we demonstrated that the Nrf2/Keap1 axis represses EIAV replication via two independent molecular mechanisms: directly increasing antioxidant enzymes to promote effective cellular resistance against EIAV infection, and repression of Rev-mediated RNA transport through direct interaction between Keap1 and Rev. Together, these data suggest that activation of the Nrf2/Keap1 axis mediates a passive defensive response to combat EIAV infection. The Nrf2/Keap1 axis could be a potential target for developing strategies for combating EIAV infection.

Highlights

Equine infectious anemia virus (EIAV), an equine lentivirus, causes persistent infection characterized by recurring febrile episodes associated with EIA clinical signs [1,2]
We report that the nuclear factor erythroid 2-related factor 2 (Nrf2)/Keap1 axis acts as an antiviral effector on EIAV replication through two-way regulation of Rev
EIAV-Rev activates the Nrf2/Keap1 axis through a competitive interaction with Keap1, and promotes the transcription of cytoprotective genes implicated in the antiviral response

Summary

Introduction

Equine infectious anemia virus (EIAV), an equine lentivirus, causes persistent infection characterized by recurring febrile episodes associated with EIA clinical signs [1,2]. Unlike hosts with infections caused by other lentiviruses, most horses infected with EIAV become lifelong inapparent EIAV carriers by eliciting immune control over virus replication [3,4,5]. An attenuated EIAV vaccine was developed through long-term passaging in equine macrophages in vitro and has successfully controlled the EIA epidemic in China, indicating that protective immunity can be induced after virus infection [5,6,7]. EIAV has been widely accepted as a system for identifying potential immune control over lentiviruses [1,8,9]. Elucidation of the innate cellular defenses during EIAV infection could facilitate comprehension of the interplay between immune control and EIAV infection

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