Rapid spread of a SARS-CoV-2 Delta variant with a frameshift deletion in ORF7a

Mapping Intimacies ◽

10.1101/2021.08.18.21262089 ◽

2021 ◽

Author(s):

Charles S.P. Foster ◽

William D Rawlinson

Keyword(s):

Frameshift Mutation ◽

Index Case ◽

Variant Calling ◽

Selective Advantage ◽

Restriction Factor ◽

Host Restriction ◽

Host Restriction Factor ◽

Frameshift Deletion ◽

Rapid Spread ◽

The Common

Australia is currently experiencing COVID-19 outbreaks from infection with SARS-CoV-2 Delta variants (B.1.617.2, AY.3). Analysis of the index case reveals a sub-consensus level of sequencing reads (~25%) that support a 17-nucleotide deletion in ORF7a (ORF7aΔ17del). ORF7aΔ17del induces a frameshift mutation in ORF7a, which truncates the peptide and potentially leads to reduced suppression of host restriction factor BST-2/CD317/Tetherin. Despite this, the mutation has rapidly become represented at the consensus level in subsequent cases: approximately 72% of SARS-CoV-2 genomes in the Australian outbreak possess ORF7aΔ17del, and 99.7% (1534/1538) of Delta genomes on GISAID with ORF7aΔ17del originate from the current Australian outbreak (5 August 2021). The global abundance of this mutation might be underestimated given the difficulty of variant calling software correctly calling insertion/deletions (indels), the common inability of phylogenetics software to take indels into account, and the tendency of GISAID to not release submissions that contain a frameshift mutation (unless specifically requested). Overall, the rapid increase of persistent ORF7aΔ17del variants is concerning, and suggests either a chance founder effect with a neutral mutation yet to be purged, or that the ORF7aΔ17del mutation provides a direct selective advantage.

Download Full-text

Host restriction factor A3G inhibits the replication of Enterovirus D68 through competitively binding 5’ UTR with PCBP1

Journal of Virology ◽

10.1128/jvi.01708-21 ◽

2021 ◽

Author(s):

Zhaolong Li ◽

Xu Yang ◽

Zhilei Zhao ◽

Xin Liu ◽

Wenyan Zhang

Keyword(s):

Broad Spectrum ◽

Enterovirus 71 ◽

Host Protein ◽

General Mechanism ◽

Restriction Factor ◽

Nucleic Acid Binding ◽

Structural Protein ◽

Stem Loop ◽

Host Restriction ◽

Host Restriction Factor

The host restriction factor APOBEC3G (A3G) presents extensively inhibition on a variety of viruses, including retroviruses, DNA and RNA viruses. Our recent study showed that A3G inhibits enterovirus 71 (EV71) and coxsackievirus A16 (CA16) via competitively binding 5’UTR with the host protein poly(C)-binding protein 1 (PCBP1) that is required for multiple EVs replication. However, in addition to EV71 and CA16, whether A3G inhibits other EVs has not been investigated. Here, we demonstrate that A3G could inhibit EVD68 replication, which needs PCBP1 for its replication, but not CA6 that PCBP1 is dispensable for CA6 replication. Further investigation revealed that nucleic acid binding activity of A3G is required for EVD68 restriction, which is similar to the mechanism presented in EV71 restriction. Mechanistically, A3G competitively binds to the cloverleaf (1–123) and the stem-loop IV (234-446) domains of EVD68 5’UTR with PCBP1, thereby inhibiting the 5'UTR activity of EVD68, whereas A3G doesn’t interact with CA6 5’UTR results in no effect on CA6 replication. Moreover, non-structural protein 2C encoded by EVD68 overcomes A3G suppression through inducing A3G degradation via the autophagy-lysosome pathway. Our finding revealed that A3G might have broad spectrum antiviral activity against multiple EVs through the general mechanism, which might provide important information for the development of anti-EVs strategy. Importance As the two major pathogens causing hand, food, and mouth disease (HFMD), EV71 and CA16 attract more attention for the discovery of pathogenesis, the involvement of cellular proteins and so on. However, other EVs such as CA6 or EVD68 constantly occurred sporadic or might spread widely in recent years worldwide. Therefore, more information related to these EVs needs to be further investigated so as to develop broad-spectrum anti-EVs inhibitor. In this study, we first reveal that PCBP1 involved in PV and EV71 virus replication, also is required for the replication of EVD68 but not CA6. Then we found that the host restriction factor A3G specifically inhibits the replication of EVD68 but not CA6 via competitively binding to the 5’UTR of EVD68 with PCBP1. Our findings broaden the knowledge related to EVs replication and the interplay between EVs and host factors.

Download Full-text

Host Restriction Factor Screening: Let the Virus Do the Work

Cell Host & Microbe ◽

10.1016/j.chom.2013.08.014 ◽

2013 ◽

Vol 14 (3) ◽

pp. 229-231 ◽

Cited By ~ 2

Author(s):

Michael S. Diamond ◽

John W. Schoggins

Keyword(s):

Restriction Factor ◽

Factor Screening ◽

Host Restriction ◽

Host Restriction Factor

Download Full-text

B-Cell Lymphoma 6 (BCL6) Is a Host Restriction Factor That Can Suppress HBV Gene Expression and Modulate Immune Responses

Frontiers in Microbiology ◽

10.3389/fmicb.2018.03253 ◽

2019 ◽

Vol 9 ◽

Author(s):

Chun-Ta Lin ◽

Yue-Ting Hsieh ◽

Yeng-Jey Yang ◽

Shih-Hui Chen ◽

Cheng-Hsuan Wu ◽

...

Keyword(s):

Gene Expression ◽

Immune Responses ◽

B Cell ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Restriction Factor ◽

Host Restriction ◽

Host Restriction Factor

Download Full-text

A double-stranded RNA platform is required for the interaction between a host restriction factor and the NS1 protein of influenza A virus

Nucleic Acids Research ◽

10.1093/nar/gkz1094 ◽

2019 ◽

Vol 48 (1) ◽

pp. 304-315 ◽

Cited By ~ 3

Author(s):

Guifang Chen ◽

Li-Chung Ma ◽

Shanshan Wang ◽

Ryan L Woltz ◽

Emily M Grasso ◽

...

Keyword(s):

Amino Acid ◽

Influenza A ◽

Binding Activity ◽

Restriction Factor ◽

Amino Acid Residues ◽

Ns1 Protein ◽

Double Stranded Rna ◽

Host Restriction ◽

Host Restriction Factor ◽

Dsrna Binding

Abstract Influenza A viruses cause widespread human respiratory disease. The viral multifunctional NS1 protein inhibits host antiviral responses. This inhibition results from the binding of specific cellular antiviral proteins at various positions on the NS1 protein. Remarkably, binding of several proteins also requires the two amino-acid residues in the NS1 N-terminal RNA-binding domain (RBD) that are required for binding double-stranded RNA (dsRNA). Here we focus on the host restriction factor DHX30 helicase that is countered by the NS1 protein, and establish why the dsRNA-binding activity of NS1 is required for its binding to DHX30. We show that the N-terminal 152 amino-acid residue segment of DHX30, denoted DHX30N, possesses all the antiviral activity of DHX30 and contains a dsRNA-binding domain, and that the NS1-DHX30 interaction in vivo requires the dsRNA-binding activity of both DHX30N and the NS1 RBD. We demonstrate why this is the case using bacteria-expressed proteins: the DHX30N-NS1 RBD interaction in vitro requires the presence of a dsRNA platform that binds both NS1 RBD and DHX30N. We propose that a similar dsRNA platform functions in interactions of the NS1 protein with other proteins that requires these same two amino-acid residues required for NS1 RBD dsRNA-binding activity.

Download Full-text

Inhibition of Avian Influenza A Virus Replication in Human Cells by Host Restriction Factor TUFM Is Correlated with Autophagy

mBio ◽

10.1128/mbio.00481-17 ◽

2017 ◽

Vol 8 (3) ◽

Cited By ~ 19

Author(s):

Shu-Ming Kuo ◽

Chi-Jene Chen ◽

Shih-Cheng Chang ◽

Tzu-Jou Liu ◽

Yi-Hsiang Chen ◽

...

Keyword(s):

Influenza Virus ◽

Avian Influenza ◽

Virus Replication ◽

Influenza A ◽

Inhibitory Effect ◽

Human Cells ◽

Restriction Factor ◽

Influenza A Viruses ◽

Host Restriction ◽

Host Restriction Factor

ABSTRACT Avian influenza A viruses generally do not replicate efficiently in human cells, but substitution of glutamic acid (Glu, E) for lysine (Lys, K) at residue 627 of avian influenza virus polymerase basic protein 2 (PB2) can serve to overcome host restriction and facilitate human infectivity. Although PB2 residue 627 is regarded as a species-specific signature of influenza A viruses, host restriction factors associated with PB2627E have yet to be fully investigated. We conducted immunoprecipitation, followed by differential proteomic analysis, to identify proteins associating with PB2627K (human signature) and PB2627E (avian signature) of influenza A/WSN/1933(H1N1) virus, and the results indicated that Tu elongation factor, mitochondrial (TUFM), had a higher binding affinity for PB2627E than PB2627K in transfected human cells. Stronger binding of TUFM to avian-signature PB2590G/591Q and PB2627E in the 2009 swine-origin pandemic H1N1 and 2013 avian-origin H7N9 influenza A viruses was similarly observed. Viruses carrying avian-signature PB2627E demonstrated increased replication in TUFM-deficient cells, but viral replication decreased in cells overexpressing TUFM. Interestingly, the presence of TUFM specifically inhibited the replication of PB2627E viruses, but not PB2627K viruses. In addition, enhanced levels of interaction between TUFM and PB2627E were noted in the mitochondrial fraction of infected cells. Furthermore, TUFM-dependent autophagy was reduced in TUFM-deficient cells infected with PB2627E virus; however, autophagy remained consistent in PB2627K virus-infected cells. The results suggest that TUFM acts as a host restriction factor that impedes avian-signature influenza A virus replication in human cells in a manner that correlates with autophagy. IMPORTANCE An understanding of the mechanisms that influenza A viruses utilize to shift host tropism and the identification of host restriction factors that can limit infection are both critical to the prevention and control of emerging viruses that cross species barriers to target new hosts. Using a proteomic approach, we revealed a novel role for TUFM as a host restriction factor that exerts an inhibitory effect on avian-signature PB2627E influenza virus propagation in human cells. We further found that increased TUFM-dependent autophagy correlates with the inhibitory effect on avian-signature influenza virus replication and may serve as a key intrinsic mechanism to restrict avian influenza virus infection in humans. These findings provide new insight regarding the TUFM mitochondrial protein and may have important implications for the development of novel antiviral strategies. IMPORTANCE An understanding of the mechanisms that influenza A viruses utilize to shift host tropism and the identification of host restriction factors that can limit infection are both critical to the prevention and control of emerging viruses that cross species barriers to target new hosts. Using a proteomic approach, we revealed a novel role for TUFM as a host restriction factor that exerts an inhibitory effect on avian-signature PB2627E influenza virus propagation in human cells. We further found that increased TUFM-dependent autophagy correlates with the inhibitory effect on avian-signature influenza virus replication and may serve as a key intrinsic mechanism to restrict avian influenza virus infection in humans. These findings provide new insight regarding the TUFM mitochondrial protein and may have important implications for the development of novel antiviral strategies.

Download Full-text

The Myb-related protein MYPOP is a novel intrinsic host restriction factor of oncogenic human papillomaviruses

Oncogene ◽

10.1038/s41388-018-0398-6 ◽

2018 ◽

Vol 37 (48) ◽

pp. 6275-6284 ◽

Cited By ~ 6

Author(s):

Elena Wüstenhagen ◽

Fatima Boukhallouk ◽

Inka Negwer ◽

Krishnaraj Rajalingam ◽

Frank Stubenrauch ◽

...

Keyword(s):

Human Papillomaviruses ◽

Restriction Factor ◽

Related Protein ◽

Host Restriction ◽

Host Restriction Factor

Download Full-text

The Evolutionary Histories of Antiretroviral Proteins SERINC3 and SERINC5 Do Not Support an Evolutionary Arms Race in Primates

Journal of Virology ◽

10.1128/jvi.00972-16 ◽

2016 ◽

Vol 90 (18) ◽

pp. 8085-8089 ◽

Cited By ~ 26

Author(s):

Ben Murrell ◽

Thomas Vollbrecht ◽

John Guatelli ◽

Joel O. Wertheim

Keyword(s):

Viral Infections ◽

Arms Race ◽

Restriction Factor ◽

Restriction Factors ◽

Arms Races ◽

Host Restriction ◽

Host Restriction Factor ◽

Novel Host ◽

Evolutionary Arms Race ◽

Hiv 1

ABSTRACTMolecular evolutionary arms races between viruses and their hosts are important drivers of adaptation. These Red Queen dynamics have been frequently observed in primate retroviruses and their antagonists, host restriction factor genes, such as APOBEC3F/G, TRIM5-α, SAMHD1, and BST-2. Host restriction factors have experienced some of the most intense and pervasive adaptive evolution documented in primates. Recently, two novel host factors, SERINC3 and SERINC5, were identified as the targets of HIV-1 Nef, a protein crucial for the optimal infectivity of virus particles. Here, we compared the evolutionary fingerprints of SERINC3 and SERINC5 to those of other primate restriction factors and to a set of other genes with diverse functions. SERINC genes evolved in a manner distinct from the canonical arms race dynamics seen in the other restriction factors. Despite their antiviral activity against HIV-1 and other retroviruses, SERINC3 and SERINC5 have a relatively uneventful evolutionary history in primates.IMPORTANCERestriction factors are host proteins that block viral infection and replication. Many viruses, like HIV-1 and related retroviruses, evolved accessory proteins to counteract these restriction factors. The importance of these interactions is evidenced by the intense adaptive selection pressures that dominate the evolutionary histories of both the host and viral genes involved in this so-called arms race. The dynamics of these arms races can point to mechanisms by which these viral infections can be prevented. Two human genes, SERINC3 and SERINC5, were recently identified as targets of an HIV-1 accessory protein important for viral infectivity. Unexpectedly, we found that these SERINC genes, unlike other host restriction factor genes, show no evidence of a recent evolutionary arms race with viral pathogens.

Download Full-text