scholarly journals Combinatorial mutagenesis of rapidly-evolving residues yields super-restrictor antiviral proteins

2019 ◽  
Author(s):  
Rossana Colón-Thillet ◽  
Emily Hsieh ◽  
Laura Graf ◽  
Richard N McLaughlin ◽  
Janet M. Young ◽  
...  
Keyword(s):  
Positive Selection ◽  
Influenza A ◽  
Adaptive Landscape ◽  
Antiviral Protein ◽  
Arms Races ◽  
Protein Protein Interaction ◽  
H5n1 Influenza ◽  
Naturally Occurring ◽  
Antiviral Proteins ◽  
Combinatorial Mutagenesis

AbstractAntagonistic interactions drive host-virus evolutionary arms-races, which often manifest as recurrent amino acid changes (i.e., positive selection) at their protein-protein interaction interfaces. Here, we investigated whether combinatorial mutagenesis of positions under positive selection in a host antiviral protein could enhance its restrictive properties. We tested ~700 variants of human MxA, generated by combinatorial mutagenesis, for their ability to restrict Thogoto orthomyxovirus (THOV). We identified MxA super-restrictors with increased binding to THOV NP target protein and 10-fold higher anti-THOV restriction relative to wild-type human MxA, the most potent naturally-occurring anti-THOV restrictor identified. Our findings reveal a means to elicit super-restrictor antiviral proteins by leveraging signatures of positive selection. Although some MxA super-restrictors of THOV were impaired in their restriction of H5N1 influenza A virus (IAV), other super-restrictor variants increased THOV restriction without impairment of IAV restriction. Thus, broadly acting antiviral proteins such as MxA mitigate breadth-versus-specificity tradeoffs that could otherwise constrain their adaptive landscape.

scholarly journals Mutational resilience of antiviral restriction favors primate TRIM5α in host-virus evolutionary arms races

2020 ◽  
Author(s):  
Jeannette L. Tenthorey ◽  
Candice Young ◽  
Afeez Sodeinde ◽  
Michael Emerman ◽  
Harmit S. Malik
Keyword(s):  
Immune Defense ◽  
Adaptive Landscape ◽  
Arms Races ◽  
Viral Restriction ◽  
Antiviral Function ◽  
Antiviral Proteins

ABSTRACTHost antiviral proteins engage in evolutionary arms races with viruses, in which both sides rapidly evolve at interaction interfaces to gain or evade immune defense. For example, primate TRIM5α uses its rapidly evolving “v1” loop to bind retroviral capsids, and single mutations in this loop can dramatically improve retroviral restriction. However, it is unknown whether such gains of viral restriction are rare, or if they incur loss of pre-existing function against other viruses. Using deep mutational scanning, we comprehensively measured how single mutations in the TRIM5α v1 loop affect restriction of divergent retroviruses. Unexpectedly, we found that the majority of mutations increase antiviral function. Moreover, most random mutations do not disrupt potent viral restriction, even when it is newly acquired via single adaptive substitutions. Our results indicate that TRIM5α’s adaptive landscape is remarkably broad and mutationally resilient, maximizing its chances of success in evolutionary arms races with retroviruses.

scholarly journals Mutational resilience of antiviral restriction favors primate TRIM5α in host-virus evolutionary arms races

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Jeannette L Tenthorey ◽  
Candice Young ◽  
Afeez Sodeinde ◽  
Michael Emerman ◽  
Harmit S Malik
Keyword(s):  
Immune Defense ◽  
Adaptive Landscape ◽  
Arms Races ◽  
Viral Restriction ◽  
Antiviral Function ◽  
Antiviral Proteins ◽  
Adaptive Substitution

Host antiviral proteins engage in evolutionary arms races with viruses, in which both sides rapidly evolve at interaction interfaces to gain or evade immune defense. For example, primate TRIM5α uses its rapidly evolving ‘v1’ loop to bind retroviral capsids, and single mutations in this loop can dramatically improve retroviral restriction. However, it is unknown whether such gains of viral restriction are rare, or if they incur loss of pre-existing function against other viruses. Using deep mutational scanning, we comprehensively measured how single mutations in the TRIM5α v1 loop affect restriction of divergent retroviruses. Unexpectedly, we found that the majority of mutations increase weak antiviral function. Moreover, most random mutations do not disrupt potent viral restriction, even when it is newly acquired via a single adaptive substitution. Our results indicate that TRIM5α’s adaptive landscape is remarkably broad and mutationally resilient, maximizing its chances of success in evolutionary arms races with retroviruses.

scholarly journals Effect on Virulence and Pathogenicity of H5N1 Influenza A Virus through Truncations of NS1 eIF4GI Binding Domain

2010 ◽  
Vol 202 (9) ◽  
pp. 1338-1346 ◽  
Author(s):  
Hongbo Zhou ◽  
Jiping Zhu ◽  
Jiagang Tu ◽  
Wei Zou ◽  
Yong Hu ◽  
...  
Keyword(s):  
Influenza A Virus ◽  
Influenza A ◽  
Binding Domain ◽  
H5n1 Influenza

scholarly journals Characterization of a Human H5N1 Influenza A Virus Isolated in 2003

2005 ◽  
Vol 79 (15) ◽  
pp. 9926-9932 ◽  
Author(s):  
Kyoko Shinya ◽  
Masato Hatta ◽  
Shinya Yamada ◽  
Ayato Takada ◽  
Shinji Watanabe ◽  
...  
Keyword(s):  
Hong Kong ◽  
Avian Influenza ◽  
Influenza A Virus ◽  
Influenza A ◽  
Mainland China ◽  
Virus Infections ◽  
Influenza A Viruses ◽  
H5n1 Avian Influenza Virus ◽  
H5n1 Influenza ◽  
Avian Influenza A Virus

ABSTRACT In 2003, H5N1 avian influenza virus infections were diagnosed in two Hong Kong residents who had visited the Fujian province in mainland China, affording us the opportunity to characterize one of the viral isolates, A/Hong Kong/213/03 (HK213; H5N1). In contrast to H5N1 viruses isolated from humans during the 1997 outbreak in Hong Kong, HK213 retained several features of aquatic bird viruses, including the lack of a deletion in the neuraminidase stalk and the absence of additional oligosaccharide chains at the globular head of the hemagglutinin molecule. It demonstrated weak pathogenicity in mice and ferrets but caused lethal infection in chickens. The original isolate failed to produce disease in ducks but became more pathogenic after five passages. Taken together, these findings portray the HK213 isolate as an aquatic avian influenza A virus without the molecular changes associated with the replication of H5N1 avian viruses in land-based poultry such as chickens. This case challenges the view that adaptation to land-based poultry is a prerequisite for the replication of aquatic avian influenza A viruses in humans.

scholarly journals Lethal avian influenza A (H5N1) virus replicates in pontomedullary chemosensitive neurons and depresses hypercapnic ventilatory response in mice

2019 ◽  
Vol 316 (3) ◽  
pp. L525-L536 ◽  
Author(s):  
Jianguo Zhuang ◽  
Na Zang ◽  
Chunyan Ye ◽  
Fadi Xu
Keyword(s):  
Viral Infection ◽  
Carotid Body ◽  
Influenza A ◽  
Tryptophan Hydroxylase ◽  
Ventilatory Response ◽  
Severe Depression ◽  
Infection Period ◽  
Hypercapnic Ventilatory Response ◽  
H5n1 Influenza ◽  
Neurokinin 1

The highly pathogenic H5N1 (HK483) viral infection causes a depressed hypercapnic ventilatory response (dHCVR, 20%↓) at 2 days postinfection (dpi) and death at 7 dpi in mice, but the relevant mechanisms are not fully understood. Glomus cells in the carotid body and catecholaminergic neurons in locus coeruleus (LC), neurokinin 1 receptor (NK1R)-expressing neurons in the retrotrapezoid nucleus (RTN), and serotonergic neurons in the raphe are chemosensitive and responsible for HCVR. We asked whether the dHCVR became worse over the infection period with viral replication in these cells/neurons. Mice intranasally inoculated with saline or the HK483 virus were exposed to hypercapnia for 5 min at 0, 2, 4, or 6 dpi, followed by immunohistochemistry to determine the expression of nucleoprotein of H5N1 influenza A (NP) alone and coupled with 1) tyrosine hydroxylase (TH) in the carotid body and LC, 2) NK1R in the RTN, and 3) tryptophan hydroxylase (TPH) in the raphe. HK483 viral infection blunted HCVR by ∼20, 50, and 65% at 2, 4, and 6 dpi. The NP was observed in the pontomedullary respiratory-related nuclei (but not in the carotid body) at 4 and 6 dpi, especially in 20% of RTN NK1R, 35% of LC TH, and ∼10% raphe TPH neurons. The infection significantly reduced the local NK1R or TPH immunoreactivity and population of neurons expressing NK1R or TPH. We conclude that the HK483 virus infects the pontomedullary respiratory nuclei, particularly chemosensitive neurons in the RTN, LC, and raphe, contributing to the severe depression of HCVR and respiratory failure at 6 dpi.

scholarly journals Molecular Characterization of the Hemagglutinin and Neuraminidase Genes of H5N1 Influenza A Viruses Isolated from Poultry in Vietnam from 2004 to 2005

2006 ◽  
Vol 68 (5) ◽  
pp. 527-531 ◽  
Author(s):  
Yukiko MURAMOTO ◽  
Thi Quynh Mai LE ◽  
Lien Song PHUONG ◽  
Tung NGUYEN ◽  
Thu Ha NGUYEN ◽  
...  
Keyword(s):  
Molecular Characterization ◽  
Influenza A ◽  
Influenza A Viruses ◽  
H5n1 Influenza

scholarly journals Influenza Antigens NP and M2 Confer Cross Protection to BALB/c Mice against Lethal Challenge with H1N1, Pandemic H1N1 or H5N1 Influenza A Viruses

Viruses ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 1708
Author(s):  
Nutan Mytle ◽  
Sonja Leyrer ◽  
Jon R. Inglefield ◽  
Andrea M. Harris ◽  
Thomas E. Hickey ◽  
...  
Keyword(s):  
Influenza A ◽  
Matrix Protein ◽  
Tandem Repeats ◽  
Protective Antigen ◽  
Serum Antibody ◽  
Cross Protection ◽  
Antigenic Drift ◽  
Natural Immunity ◽  
Pandemic H1n1 ◽  
H5n1 Influenza

Influenza hemagglutinin (HA) is considered a major protective antigen of seasonal influenza vaccine but antigenic drift of HA necessitates annual immunizations using new circulating HA versions. Low variation found within conserved non-HA influenza virus (INFV) antigens may maintain protection with less frequent immunizations. Conserved antigens of influenza A virus (INFV A) that can generate cross protection against multiple INFV strains were evaluated in BALB/c mice using modified Vaccinia virus Ankara (MVA)-vectored vaccines that expressed INFV A antigens hemagglutinin (HA), matrix protein 1 (M1), nucleoprotein (NP), matrix protein 2 (M2), repeats of the external portion of M2 (M2e) or as tandem repeats (METR), and M2e with transmembrane region and cytoplasmic loop (M2eTML). Protection by combinations of non-HA antigens was equivalent to that of subtype-matched HA. Combinations of NP and forms of M2e generated serum antibody responses and protected mice against lethal INFV A challenge using PR8, pandemic H1N1 A/Mexico/4108/2009 (pH1N1) or H5N1 A/Vietnam/1203/2004 (H5N1) viruses, as demonstrated by reduced lung viral burden and protection against weight loss. The highest levels of protection were obtained with NP and M2e antigens delivered as MVA inserts, resulting in broadly protective immunity in mice and enhancement of previous natural immunity to INFV A.

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