Permissive Secondary Mutations Enable the Evolution of Influenza Oseltamivir Resistance

By Jesse D. Bloom, L. Gong, David Baltimore. 2010

678 citations recorded by the source corpus.

Influenza Escape Tricks Tamiflu, or oseltamivir, has been extensively stockpiled by several governments in anticipation of a dangerous influenza pandemic. So far, its large-scale use has not been required, but, despite this, resistance has emerged in seasonal strains mediated by a single point mutation of histidine to tyrosine in the 274 residue (H274Y) of neuraminidase. When the resistant virus was first discovered in 1998, it grew poorly, but by 2008 the virus was reinvigorated and the mutation had spread worldwide in seasonal influenza. So what happened that improved viral fitness so radically? Bloom et al. (p. 1272; see the Perspective by Holmes) show that the H274Y mutation hinders the folding of the neuraminidase enzyme. In the more vigorous recent oseltamivir-resistant isolates, other mutations compensate for the deleterious effect of H274Y and restore fitness to the virus. Compensatory mutations offset the structural costs of acquiring a drug-resistance mutation in a virus. The His274→Tyr274 (H274Y) mutation confers oseltamivir resistance on N1 influenza neuraminidase but had long been thought to compromise viral fitness. However, beginning in 2007–2008, viruses containing H274Y rapidly became predominant among human seasonal H1N1 isolates. We show that H274Y decreases the amount of neuraminidase that reaches the cell surface and that this defect can be counteracted by secondary mutations that also restore viral fitness. Two such mutations occurred in seasonal H1N1 shortly before the widespread appearance of H274Y. The evolution of oseltamivir resistance was therefore enabled by “permissive” mutations that allowed the virus to tolerate subsequent occurrences of H274Y. An understanding of this process may provide a basis for predicting the evolution of oseltamivir resistance in other influenza strains.

Subfields: Epidemiology, Molecular Biology

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Epidemiology

In Molecular Biology

Citations in the corpus

Prevalence of Epistasis in the Evolution of Influenza A Surface Proteins (2011, methodology): “Although further experimental validation is required, the remarkable concordance between our statistical inferences and experimentally verified epistatic interactions [16] suggests that patterns of sequence evolution contain extremely useful information about a protein’s fitness landscape.”
Viral Phylodynamics (2013, background): “Commonly, there is a fitness trade-off between faster replication of susceptible strains in the absence of antiviral treatment and faster replication of resistant strains in the presence of antivirals [19].”
Mapping person-to-person variation in viral mutations that escape polyclonal serum targeting influenza hemagglutinin (2019, methodology): “To generate the viruses, we transfected a co-culture of 4 × 105 293T-CMV-PB1 (Bloom et al., 2010) and 0.”
Constraints Evolve: Context Dependency of Gene Effects Allows Evolution of Pleiotropy (2015, background): “…in different patterns for different traits: a neutral, so-called permissive mutation, which renders the following mutation adaptive for one trait (Bloom et al. 2010, Bridgham et al. 2009), for example, may manifest as a locally disadvantageous mutation followed by a compensatory mutation from…”
Sequence-Specific Modifications Enhance the Broad-Spectrum Antiviral Response Activated by RIG-I Agonists (2015, background): “infection but has given rise to drug-resistant mutants (2, 3).”
Systematic Identification of H274Y Compensatory Mutations in Influenza A Virus Neuraminidase by High-Throughput Screening (2012, methodology): “Whereas R194G has been described in the past (16, 31), we turned our attention to E214D, which is present in only 1.”
Epistasis in protein evolution (2016, background): “Nonspecific epistasis has also been observed for mutations that are additive with respect to other physical properties (folding, ligandbinding affinity, and enzyme activity) but are nonadditive with respect to surface expression, transcriptional activity, or fitness, simply because of the nonlinear ”
Construction, characterization, and immunization of nanoparticles that display a diverse array of influenza HA trimers (2020, methodology): “Neutralization assays were conducted using live PB1flank-eGFP virus for BSL 2 strains A/ Aichi/02/1968 (X31; H3N2), A/California/04/2009 (CA09; H1N1), A/Texas/36/1991 (TX91; H1N1), and A/Wisconsin/67/2005 (WI05; H3N2) as described [30] using reagents kindly provided by Dr.”
Computational design of trimeric influenza neutralizing proteins targeting the hemagglutinin receptor binding site (2017, background): “Resistance has evolved to widely used anti-viral drugs 13, 14 , and seasonal vaccines are unlikely to provide much if any protection against newly emerging viruses.”
Stability-mediated epistasis constrains the evolution of an influenza protein (2013, methodology): “To confirm this, we used reverse genetics (Hoffmann et al., 2000) to generate GFP-carrying viruses (Bloom et al., 2010) with the polymerase genes from Nanchang/1995 and the remaining genes from the lab-adapted A/WSN/1933 (H1N1) strain (Figure 3—figure supplement 2).”
Deep mutational scanning of SARS-CoV-2 receptor binding domain reveals constraints on folding and ACE2 binding (2020, positive): “…implies ample evolutionary potential for compensation of deleterious mutations in the ACE2 interface in a manner reminiscent of multi-step escape pathways that have been described for other viruses (Bloom et al., 2010; Friedrich et al., 2004; Gong et al., 2013; Lynch et al., 2015; Wu et al., 2017).”
Deep Mutational Scanning of SARS-CoV-2 Receptor Binding Domain Reveals Constraints on Folding and ACE2 Binding (2020, positive): “Second, there are a number of RBD mutations that enhance ACE2 affinity, which implies evolutionary potential for compensation of deleterious mutations in the ACE2 interface in a manner reminiscent of multi-step escape pathways that have been described for other viruses (Bloom et al., 2010; Friedrich”