Long-Term Virus Evolution in Nature

ABSTRACT Certain “protective” major histocompatibility complex class I (MHC-I) alleles, such as B*57 and B*27, are associated with long-term control of HIV-1 in vivo mediated by the CD8+ cytotoxic-T-lymphocyte (CTL) response. However, the mechanism of such superior protection is not fully understood. Here we combined high-throughput fitness profiling of mutations in HIV-1 Gag, in silico prediction of MHC-peptide binding affinity, and analysis of intraperson virus evolution to systematically compare differences with respect to CTL escape mutations between epitopes targeted by protective MHC-I alleles and those targeted by nonprotective MHC-I alleles. We observed that the effects of mutations on both viral replication and MHC-I binding affinity are among the determinants of CTL escape. Mutations in Gag epitopes presented by protective MHC-I alleles are associated with significantly higher fitness cost and lower reductions in binding affinity with respect to MHC-I. A linear regression model accounting for the effect of mutations on both viral replicative capacity and MHC-I binding can explain the protective efficacy of MHC-I alleles. Finally, we found a consistent pattern in the evolution of Gag epitopes in long-term nonprogressors versus progressors. Overall, our results suggest that certain protective MHC-I alleles allow superior control of HIV-1 by targeting epitopes where mutations typically incur high fitness costs and small reductions in MHC-I binding affinity. IMPORTANCE Understanding the mechanism of viral control achieved in long-term nonprogressors with protective HLA alleles provides insights for developing functional cure of HIV infection. Through the characterization of CTL escape mutations in infected persons, previous researchers hypothesized that protective alleles target epitopes where escape mutations significantly reduce viral replicative capacity. However, these studies were usually limited to a few mutations observed in vivo. Here we utilized our recently developed high-throughput fitness profiling method to quantitatively measure the fitness of mutations across the entirety of HIV-1 Gag. The data enabled us to integrate the results with in silico prediction of MHC-peptide binding affinity and analysis of intraperson virus evolution to systematically determine the differences in CTL escape mutations between epitopes targeted by protective HLA alleles and those targeted by nonprotective HLA alleles. We observed that the effects of Gag epitope mutations on HIV replicative fitness and MHC-I binding affinity are among the major determinants of CTL escape. IMPORTANCE Understanding the mechanism of viral control achieved in long-term nonprogressors with protective HLA alleles provides insights for developing functional cure of HIV infection. Through the characterization of CTL escape mutations in infected persons, previous researchers hypothesized that protective alleles target epitopes where escape mutations significantly reduce viral replicative capacity. However, these studies were usually limited to a few mutations observed in vivo. Here we utilized our recently developed high-throughput fitness profiling method to quantitatively measure the fitness of mutations across the entirety of HIV-1 Gag. The data enabled us to integrate the results with in silico prediction of MHC-peptide binding affinity and analysis of intraperson virus evolution to systematically determine the differences in CTL escape mutations between epitopes targeted by protective HLA alleles and those targeted by nonprotective HLA alleles. We observed that the effects of Gag epitope mutations on HIV replicative fitness and MHC-I binding affinity are among the major determinants of CTL escape.

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Bayesian inference of antigenic and non-antigenic variables from haemagglutination inhibition assays for influenza surveillance

Royal Society Open Science ◽

10.1098/rsos.180113 ◽

2018 ◽

Vol 5 (7) ◽

pp. 180113

Author(s):

Emmanuel S. Adabor ◽

Wilfred Ndifon

Keyword(s):

Influenza Virus ◽

Influenza A ◽

Bayesian Method ◽

Haemagglutination Inhibition ◽

Virus Evolution ◽

Influenza Viruses ◽

Influenza Surveillance ◽

Antigenic Properties ◽

Analytical Work

Haemagglutination inhibition (HI) assays are typically used for comparing and characterizing influenza viruses. Data obtained from the assays (titres) are used quantitatively to determine antigenic differences between influenza strains. However, the use of these titres has been criticized as they sometimes fail to capture accurate antigenic differences between strains. Our previous analytical work revealed how antigenic and non-antigenic variables contribute to the titres. Building on this previous work, we have developed a Bayesian method for decoupling antigenic and non-antigenic contributions to the titres in this paper. We apply this method to a compendium of HI titres of influenza A (H3N2) viruses curated from 1968 to 2016. Remarkably, the results of this fit indicate that the non-antigenic variable, which is inversely correlated with viral avidity for the red blood cells used in HI assays, oscillates during the course of influenza virus evolution, with a period that corresponds roughly to the timescale on which antigenic variants replace each other. Together, the results suggest that the new Bayesian method is applicable to the analysis of long-term dynamics of both antigenic and non-antigenic properties of influenza virus.

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Internal Disequilibria and Phenotypic Diversification during Replication of Hepatitis C Virus in a Noncoevolving Cellular Environment

Journal of Virology ◽

10.1128/jvi.02505-16 ◽

2017 ◽

Vol 91 (10) ◽

Cited By ~ 24

Author(s):

Elena Moreno ◽

Isabel Gallego ◽

Josep Gregori ◽

Adriana Lucía-Sanz ◽

María Eugenia Soria ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Virus Evolution ◽

Progeny Production ◽

Human Hepatoma Cells ◽

Cellular Environment ◽

Mutant Spectrum ◽

Phenotypic Diversification ◽

Population Equilibrium

ABSTRACT Viral quasispecies evolution upon long-term virus replication in a noncoevolving cellular environment raises relevant general issues, such as the attainment of population equilibrium, compliance with the molecular-clock hypothesis, or stability of the phenotypic profile. Here, we evaluate the adaptation, mutant spectrum dynamics, and phenotypic diversification of hepatitis C virus (HCV) in the course of 200 passages in human hepatoma cells in an experimental design that precluded coevolution of the cells with the virus. Adaptation to the cells was evidenced by increase in progeny production. The rate of accumulation of mutations in the genomic consensus sequence deviated slightly from linearity, and mutant spectrum analyses revealed a complex dynamic of mutational waves, which was sustained beyond passage 100. The virus underwent several phenotypic changes, some of which impacted the virus-host relationship, such as enhanced cell killing, a shift toward higher virion density, and increased shutoff of host cell protein synthesis. Fluctuations in progeny production and failure to reach population equilibrium at the genomic level suggest internal instabilities that anticipate an unpredictable HCV evolution in the complex liver environment. IMPORTANCE Long-term virus evolution in an unperturbed cellular environment can reveal features of virus evolution that cannot be explained by comparing natural viral isolates. In the present study, we investigate genetic and phenotypic changes that occur upon prolonged passage of hepatitis C virus (HCV) in human hepatoma cells in an experimental design in which host cell evolutionary change is prevented. Despite replication in a noncoevolving cellular environment, the virus exhibited internal population disequilibria that did not decline with increased adaptation to the host cells. The diversification of phenotypic traits suggests that disequilibria inherent to viral populations may provide a selective advantage to viruses that can be fully exploited in changing environments.

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Virus evolution in Wolbachia- infected Drosophila

Proceedings of The Royal Society B Biological Sciences ◽

10.1098/rspb.2019.2117 ◽

2019 ◽

Vol 286 (1914) ◽

pp. 20192117 ◽

Cited By ~ 2

Author(s):

Julien Martinez ◽

Gaspar Bruner-Montero ◽

Ramesh Arunkumar ◽

Sophia C. L. Smith ◽

Jonathan P. Day ◽

...

Keyword(s):

Viral Infection ◽

Virus Evolution ◽

Viral Pathogens ◽

Antiviral Effects ◽

Evolutionary Response ◽

Virus Genotypes ◽

Virus Blocking

Wolbachia , a common vertically transmitted symbiont, can protect insects against viral infection and prevent mosquitoes from transmitting viral pathogens. For this reason, Wolbachia- infected mosquitoes are being released to prevent the transmission of dengue and other arboviruses. An important question for the long-term success of these programmes is whether viruses can evolve to escape the antiviral effects of Wolbachia. We have found that Wolbachia altered the outcome of competition between strains of the DCV virus in Drosophila. However, Wolbachia still effectively blocked the virus genotypes that were favoured in the presence of the symbiont. We conclude that Wolbachia did cause an evolutionary response in viruses, but this has little or no impact on the effectiveness of virus blocking.

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Long-term virus evolution in nature

Virus as Populations ◽

10.1016/b978-0-12-816331-3.00007-6 ◽

2020 ◽

pp. 225-261

Author(s):

Esteban Domingo

Keyword(s):

Virus Evolution

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High resolution profiling of pathways of escape for SARS-CoV-2 spike-binding antibodies

10.1101/2020.11.16.385278 ◽

2020 ◽

Cited By ~ 1

Author(s):

Meghan E. Garrett ◽

Jared Galloway ◽

Helen Y. Chu ◽

Hannah L. Itell ◽

Caitlin I. Stoddard ◽

...

Keyword(s):

Viral Entry ◽

Individual Variation ◽

Protective Immunity ◽

Virus Evolution ◽

Fusion Peptide ◽

Heptad Repeat ◽

Immune Protection ◽

Repeat Region ◽

Plasma Antibody

SUMMARYDefining long-term protective immunity to SARS-CoV-2 is one of the most pressing questions of our time and will require a detailed understanding of potential ways this virus can evolve to escape immune protection. Immune protection will most likely be mediated by antibodies that bind to the viral entry protein, Spike (S). Here we used Phage-DMS, an approach that comprehensively interrogates the effect of all possible mutations on binding to a protein of interest, to define the profile of antibody escape to the SARS-CoV-2 S protein using COVID-19 convalescent plasma. Antibody binding was common in two regions: the fusion peptide and linker region upstream of the heptad repeat region 2. However, escape mutations were variable within these immunodominant regions. There was also individual variation in less commonly targeted epitopes. This study provides a granular view of potential antibody escape pathways and suggests there will be individual variation in antibody-mediated virus evolution.

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