The inherent mutational tolerance and antigenic evolvability of influenza hemagglutinin

Thyagarajan, Bargavi; Bloom, Jesse D.

doi:10.7554/elife.03300

Cited by 184 publications

(229 citation statements)

References 60 publications

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“…This lack of strong correlation is consistent with the observation that (predicted) pairing patterns evolve rapidly in most of the genome (Pollom et al, 2013) or might reflect inaccuracies in RNA structure prediction: only a minority of pairings agree between the predictions by Siegfried et al (2014) and Sükösd et al (2015). Several groups have estimated fitness costs within HIV-1 proteins using experimental approaches (Martinez-Picado and Martinez, 2008;Rihn et al, 2015;Thyagarajan and Bloom, 2014). Our estimates presented here are complementary to those studies in two ways.…”

Section: Discussionsupporting

confidence: 86%

In-vivo mutation rates and fitness landscape of HIV-1

Zanini

Puller

Brodin

et al. 2016

Preprint

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Mutation rates and fitness costs of deleterious mutations are difficult to measure in vivo but essential for a quantitative understanding of evolution. Using whole genome deep sequencing data from longitudinal samples during untreated HIV-1 infection, we estimated mutation rates and fitness costs in HIV-1 from the temporal dynamics of genetic variation. At approximately neutral sites, mutations accumulate with a rate of 1.2 × 10 −5 per site per day, in agreement with the rate measured in cell cultures. The rate from G to A is largest, followed by the other transitions C to T, T to C, and A to G, while transversions are more rare. At non-neutral sites, most mutations reduce virus replication; using a model of mutation selection balance, we estimated the fitness cost of mutations at every site in the HIV-1 genome. About half of all nonsynonymous mutations have large fitness costs (greater than 10%), while most synonymous mutations have costs below 1%. The cost of synonymous mutations is especially low in most of gag and pol, while much higher costs are observed in important RNA structures and regulatory regions. The intrapatient fitness cost estimates are consistent across multiple patients, suggesting that the deleterious part of the fitness landscape is universal and explains a large fraction of global HIV-1 group M diversity. IntroductionHIV-1 evolves rapidly within individual hosts: mutations allow it to evade immune predation but can also impair viral replication. Genetic changes arise during reverse transcription, during forward transcription by the human RNA polymerase II, or are caused by the innate immune system (Abram et al., 2010;Cuevas et al., 2015;Malim, 2009;Mansky and Temin, 1995). These changes are the source of genetic diversity, from which selection amplifies beneficial variants and filters deleterious mutations. Characterization of the mutation rate matrix and the genome wide landscape of fitness effects is a prerequisite a quantitative understanding of the evolutionary dynamics of HIV and for rational design of both vaccines and resistance proof drugs.The majority of mutations are deleterious, some mutations are neutral and have little or no effect, and a minority of mutations are beneficial. While beneficial mutations rapidly spread through the virus population within a patient, deleterious mutations stay at low frequency in a balance between mutation and selection. Beneficial mutations are often patient-specific and mediate escape from cytotoxic T-lymphocytes (CTL) and neutralizing antibodies (Bar et al., 2012;Goonetilleke et al., 2009;Walker and McMichael, 2012). At the same time, substitutions in response to immune selection are expected to lower intrinsic viral fitness; host-specific adaptation is a tradeoff between immune evasion and fitness costs of escape mutations.Since HIV-1 proteins serve the same function in different hosts, the landscape of fitness costs might be expected to be similar in different hosts. However, the effect of a particular mutation can depend on other sites in the...

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Section: Discussionsupporting

confidence: 86%

In-vivo mutation rates and fitness landscape of HIV-1

Zanini

Puller

Brodin

et al. 2016

Preprint

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“…For example, due to a lack of significant antigenic drift, there has not been a need to reformulate the monovalent YFV 17D vaccine, even after 60ϩ years of use (195). Many factors may modulate viral antigenic evolution, including differences in virus host range (196) and the inherent mutational tolerance of virus surface glycoproteins (197,198).…”

Section: Fig 4 Flavivirus Entry and Mechanisms Of Antibody-mediated Nmentioning

confidence: 99%

Deconstructing the Antiviral Neutralizing-Antibody Response: Implications for Vaccine Development and Immunity

VanBlargan

Goo

Pierson

2016

Microbiol Mol Biol Rev

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SUMMARY The antibody response plays a key role in protection against viral infections. While antiviral antibodies may reduce the viral burden via several mechanisms, the ability to directly inhibit (neutralize) infection of cells has been extensively studied. Eliciting a neutralizing-antibody response is a goal of many vaccine development programs and commonly correlates with protection from disease. Considerable insights into the mechanisms of neutralization have been gained from studies of monoclonal antibodies, yet the individual contributions and dynamics of the repertoire of circulating antibody specificities elicited by infection and vaccination are poorly understood on the functional and molecular levels. Neutralizing antibodies with the most protective functionalities may be a rare component of a polyclonal, pathogen-specific antibody response, further complicating efforts to identify the elements of a protective immune response. This review discusses advances in deconstructing polyclonal antibody responses to flavivirus infection or vaccination. Our discussions draw comparisons to HIV-1, a virus with a distinct structure and replication cycle for which the antibody response has been extensively investigated. Progress toward deconstructing and understanding the components of polyclonal antibody responses identifies new targets and challenges for vaccination strategies.

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“…The last few years have also seen the description of libraries of replication-competent virus mutants generated by adapting plasmid-based viral reversegenetics systems to accommodate libraries of mutagenized plasmids [31][32][33][34][35]. We utilized virus libraries created by melding these two techniques to create influenza viruses carrying all HA amino-acid point mutations compatible with viral replication [31,32].…”

Section: Resultsmentioning

confidence: 99%

Complete mapping of viral escape from neutralizing antibodies

Doud

Hensley

Bloom

2016

Preprint

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Identifying viral mutations that confer escape from antibodies is crucial for understanding the interplay between immunity and viral evolution. We describe a high-throughput approach to quantify the selection that monoclonal antibodies exert on all single amino-acid mutations to a viral protein. This approach, mutational antigenic profiling, involves creating all replication-competent protein variants of a virus, selecting with antibody, and using deep sequencing to identify enriched mutations. We use mutational antigenic profiling to comprehensively identify mutations that enable influenza virus to escape four monoclonal antibodies targeting hemagglutinin, and validate key findings with neutralization assays. We find remarkable mutation-level idiosyncrasy in antibody escape: for instance, at a single residue targeted by two antibodies, some mutations escape both antibodies while other mutations escape only one or the other. Because mutational antigenic profiling rapidly maps all mutations selected by an antibody, it is useful for elucidating immune specificities and interpreting the antigenic consequences of viral genetic variation.

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The inherent mutational tolerance and antigenic evolvability of influenza hemagglutinin

Cited by 184 publications

References 60 publications

In-vivo mutation rates and fitness landscape of HIV-1

In-vivo mutation rates and fitness landscape of HIV-1

Deconstructing the Antiviral Neutralizing-Antibody Response: Implications for Vaccine Development and Immunity

Complete mapping of viral escape from neutralizing antibodies

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