Paramyxovirus V proteins interact with the RNA helicase LGP2 to inhibit RIG-I-dependent interferon induction

This work was supported by the Wellcome Trust (grant AL087751/B)RIG-I and mda-5 are activated by viral RNA and stimulate type I interferon production. Laboratory of genetics and physiology 2 (LGP2) shares homology with RIG-I and mda-5 but lacks the CARD domains required for signaling. The V proteins of paramyxoviruses limit interferon induction by binding mda-5 and preventing its activation; however, they do not bind RIG-I and have not been considered inhibitors of RIG-I signaling. Here we uncover a novel mechanism of RIG-I inhibition in which the V protein of parainfluenzavirus type 5 (PIV5; formerly known as simian virus type 5 [SV5]) interacts with LGP2 and cooperatively inhibits induction by RIG-I ligands. A complex between RIG-I and LGP2 is observed in the presence of PIV5-V, and we propose that this complex is refractory to activation by RIG-I ligands. The V proteins from other paramyxoviruses also bind LGP2 and demonstrate LGP2-dependent inhibition of RIG-I signaling. This is significant, because it demonstrates a general mechanism for the targeting of the RIG-I pathway by paramyxoviruses.Publisher PDFPeer reviewe

Innate Intracellular Antiviral Responses Restrict the Amplification of Defective Virus Genomes of Parainfluenza Virus 5.

During the replication of parainfluenza virus 5 (PIV5), copyback defective virus genomes (DVGs) are erroneously produced and are packaged into "infectious" virus particles. Copyback DVGs are the primary inducers of innate intracellular responses, including the interferon (IFN) response. While DVGs can interfere with the replication of nondefective (ND) virus genomes and activate the IFN-induction cascade before ND PIV5 can block the production of IFN, we demonstrate that the converse is also true, i.e., high levels of ND virus can block the ability of DVGs to activate the IFN-induction cascade. By following the replication and amplification of DVGs in A549 cells that are deficient in a variety of innate intracellular antiviral responses, we show that DVGs induce an uncharacterized IFN-independent innate response(s) that limits their replication. High-throughput sequencing was used to characterize the molecular structure of copyback DVGs. While there appears to be no sequence-specific break or rejoining points for the generation of copyback DVGs, our findings suggest there are region, size, and/or structural preferences selected for during for their amplification.IMPORTANCE Copyback defective virus genomes (DVGs) are powerful inducers of innate immune responses both in vitro and in vivo They impact the outcome of natural infections, may help drive virus-host coevolution, and promote virus persistence. Due to their potent interfering and immunostimulatory properties, DVGs may also be used therapeutically as antivirals and vaccine adjuvants. However, little is known of the host cell restrictions which limit their amplification. We show here that the generation of copyback DVGs readily occurs during parainfluenza virus 5 (PIV5) replication, but that their subsequent amplification is restricted by the induction of innate intracellular responses. Molecular characterization of PIV5 copyback DVGs suggests that while there are no genome sequence-specific breaks or rejoin points for the generation of copyback DVGs, genome region, size, and structural preferences are selected for during their evolution and amplification

Reductive pairs arising from representations

We study the question of when a given rational representation of a reductive group G gives rise to a reductive pair (GL(V ), ρ(G)), presenting complete classifications when ρ is the representation afforded by a simple module for the group SL2 (K), or a symmetric power of the natural module (the induced or dual Weyl modules for this group), where K is an algebraically closed field of any positive characteristic. We also present several classes of examples for the group SL3 (K) in some small characteristics, along with results allowing new examples to be generated

13q32.1 as a candidate region for physiological anisocoria

ABSTRACT Background. Physiological anisocoria is an asymmetry of pupil size in the absence of pathology. Methods. Images of the pupils under standard illumination were collected in the course of a whole-genome association study of a range of visual functions in 1060 healthy adults. DNA for each participant was extracted from saliva samples. Results. We found no relationship between anisocoria and the difference in refraction between the eyes, nor between anisocoria and difference in acuity. There was a small but significant relationship with lightness of the iris, in that the eye with the smaller pupil was associated with the lighter iris. There was a strong association between anisocoria and a local region of chromosome 13 (13q32.1), a region lying between the genes GPR180 and SOX21. The strongest association was with the single nucleotide polymorphism rs9524583. Conclusion. The very specific region associated with anisocoria is one where microdeletions (or microduplications) are known to lead to abnormal development of pupil dilator muscle and hence to the autosomal dominant condition of microcoria. It is possible that alterations at 13q32.1 act by altering the expression of SOX21, which encodes a nuclear transcription factor.Gatsby Charitable Foundation Gonville and Caius Colleg

A population study of binocular function.

As part of a genome-wide association study (GWAS) of perceptual traits in healthy adults, we measured stereo acuity, the duration of alternative percepts in binocular rivalry and the extent of dichoptic masking in 1060 participants. We present the distributions of the measures, the correlations between measures, and their relationships to other psychophysical traits. We report sex differences, and correlations with age, interpupillary distance, eye dominance, phorias, visual acuity and personality. The GWAS, using data from 988 participants, yielded one genetic association that passed a permutation test for significance: The variant rs1022907 in the gene VTI1A was associated with self-reported ability to see autostereograms. We list a number of other suggestive genetic associations (p<10(-5)).This work was supported by the Gatsby Charitable Foundation (GAT2903). J.B. was supported by a fellowship from Gonville and Caius College.This is the author accepted manuscript. The final version is available from Elsevier via http://dx.doi.org/10.1016/j.visres.2015.02.01

Failure to activate the IFN-beta promoter by a paramyxovirus lacking an interferon antagonist

It is generally thought that pathogen-associated molecular patterns (PAMPs) responsible for triggering interferon (IFN) induction are produced during virus replication and, to limit the activation of the IFN response by these PAMPs, viruses encode antagonists of IFN induction. Here we have studied the induction of IFN by parainfluenza virus type 5 (PIV5) at the single-cell level, using a cell line expressing GFP under the control of the IFN-β promoter. We demonstrate that a recombinant PIV5 (termed PIV5-VΔC) that lacks a functional V protein (the viral IFN antagonist) does not activate the IFN-β promoter in the majority of infected cells. We conclude that viral PAMPs capable of activating the IFN induction cascade are not produced or exposed during the normal replication cycle of PIV5, and suggest instead that defective viruses are primarily responsible for inducing IFN during PIV5 infection in this syste

Sensitivity of African swine fever virus to type I interferon is linked to genes within multigene families 360 and 505.

African swine fever virus (ASFV) causes a lethal haemorrhagic disease of pigs. There are conflicting reports on the role of interferon in ASFV infection. We therefore analysed the interaction of ASFV with porcine interferon, in vivo and in vitro. Virulent ASFV induced biologically active IFN in the circulation of pigs from day 3-post infection, whereas low virulent OUR T88/3, which lacks genes from multigene family (MGF) 360 and MGF505, did not. Infection of porcine leucocytes enriched for dendritic cells, with ASFV, in vitro, induced high levels of interferon, suggesting a potential source of interferon in animals undergoing acute ASF. Replication of OUR T88/3, but not virulent viruses, was reduced in interferon pretreated macrophages and a recombinant virus lacking similar genes to those absent in OUR T88/3 was also inhibited. These findings suggest that as well as inhibiting the induction of interferon, MGF360 and MGF505 genes also enable ASFV to overcome the antiviral state

The V Proteins of Simian Virus 5 and Other Paramyxoviruses Inhibit Induction of Interferon-β

AbstractIn this article we show that the paramyxovirus SV5 is a poor inducer of interferon-β (IFN-β). This inefficient induction is a consequence of the expression of an intact viral V protein. In the absence of the viral V protein cysteine-rich C-terminal domain, IFN-β mRNA is strongly induced and the transcription factors NF-κB and IRF-3 are activated significantly. The V protein can work in isolation from SV5 to block intracellular dsRNA signaling. The mechanism of block to dsRNA signaling is distinct from that previously observed for blocking IFN signaling in that proteolysis of candidate factors cannot be detected, and furthermore, the respective blocks require distinct protein domains. Blocking of the induction of IFN-β by dsRNA requires the C-terminal cysteine-rich domain, a feature that is highly conserved among paramyxoviruses. We demonstrate that the V proteins from other paramyxoviruses have equivalent functions and speculate that limiting the yield of IFN-β during infection may be a general property of paramyxoviruses