scholarly journals Tuning the course of evolution on the biophysical fitness landscape of an RNA virus

2016 ◽  
Author(s):  
Assaf Rotem ◽  
Adrian W.R. Serohijos ◽  
Connie B. Chang ◽  
Joshua T. Wolfe ◽  
Audrey E. Fischer ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Fitness Landscape ◽  
Rna Virus ◽  
Viral Evolution ◽  
Quantitative Description ◽  
Neutralizing Antibody ◽  
Viral Population ◽  
Evolutionary Pathway ◽  
Evolutionary Forces ◽  
Selection For

ABSTRACTPredicting viral evolution remains a major challenge with profound implications for public health. Viral evolutionary pathways are determined by the fitness landscape, which maps viral genotype to fitness. However, a quantitative description of the landscape and the evolutionary forces on it remain elusive. Here, we apply a biophysical fitness model based on capsid folding stability and antibody binding affinity to predict the evolutionary pathway of norovirus escaping a neutralizing antibody. The model is validated by experimental evolution in bulk culture and in a drop-based microfluidics device, the “Evolution Chip”, which propagates millions of independent viral sub-populations. We demonstrate that along the axis of binding affinity, selection for escape variants and drift due to random mutations have the same direction. However, along folding stability, selection and drift are opposing forces whose balance is tuned by viral population size. Our results demonstrate that predictable epistatic tradeoffs shape viral evolution.

scholarly journals Resolving genetic linkage reveals patterns of selection in HIV-1 evolution

2019 ◽  
Author(s):  
Muhammad S. Sohail ◽  
Raymond H. Y. Louie ◽  
Matthew R. McKay ◽  
John P. Barton
Keyword(s):  
Neutralizing Antibodies ◽  
Genetic Linkage ◽  
Time Series Data ◽  
Quantitative Description ◽  
Viral Population ◽  
Series Data ◽  
Weak Selection ◽  
Clonal Interference ◽  
Selection For ◽  
Hiv 1

Identifying the genetic drivers of adaptation is a necessary step in understanding the dynamics of rapidly evolving pathogens and cancer. However, signals of selection are obscured by the complex, stochastic nature of evolution. Pervasive effects of genetic linkage, including genetic hitchhiking and clonal interference between beneficial mutants, challenge our ability to distinguish the selective effect of individual mutations. Here we describe a method to infer selection from genetic time series data that systematically resolves the confounding effects of genetic linkage. We applied our method to investigate patterns of selection in intrahost human immunodeficiency virus (HIV)-1 evolution, including a case in an individual who develops broadly neutralizing antibodies (bnAbs). Most variants that arise are observed to have negligible effects on inferred selection at other sites, but a small minority of highly influential variants have strong and far-reaching effects. In particular, we found that accounting for linkage is crucial for estimating selection due to clonal interference between escape mutants and other variants that sweep rapidly through the population. We observed only modest selection for antibody escape, in contrast with strong selection for escape from CD8+ T cell responses. Weak selection for escape from antibody responses may facilitate bnAb development by diversifying the viral population. Our results provide a quantitative description of the evolution of HIV-1 in response to host immunity, including selection on the viral population that accompanies bnAb development. More broadly, our analysis argues for the importance of resolving linkage effects in studies of natural selection.

scholarly journals Efficient escape from local optima in a highly rugged fitness landscape by evolving RNA virus populations

2016 ◽  
Vol 283 (1836) ◽  
pp. 20160984 ◽  
Author(s):  
Héctor Cervera ◽  
Jasna Lalić ◽  
Santiago F. Elena
Keyword(s):  
Fitness Landscape ◽  
Rna Virus ◽  
Viral Evolution ◽  
Basin Of Attraction ◽  
Local Optimum ◽  
Historical Contingency ◽  
Recombination Rates ◽  
Local Optima ◽  
Adaptive Landscapes ◽  
Chance Events

Predicting viral evolution has proven to be a particularly difficult task, mainly owing to our incomplete knowledge of some of the fundamental principles that drive it. Recently, valuable information has been provided about mutation and recombination rates, the role of genetic drift and the distribution of mutational, epistatic and pleiotropic fitness effects. However, information about the topography of virus' adaptive landscapes is still scarce, and to our knowledge no data has been reported so far on how its ruggedness may condition virus' evolvability. Here, we show that populations of an RNA virus move efficiently on a rugged landscape and scape from the basin of attraction of a local optimum. We have evolved a set of Tobacco etch virus genotypes located at increasing distances from a local adaptive optimum in a highly rugged fitness landscape, and we observed that few evolved lineages remained trapped in the local optimum, while many others explored distant regions of the landscape. Most of the diversification in fitness among the evolved lineages was explained by adaptation, while historical contingency and chance events contribution was less important. Our results demonstrate that the ruggedness of adaptive landscapes is not an impediment for RNA viruses to efficiently explore remote parts of it.

scholarly journals Fitness-Balanced Escape Determines Resolution of Dynamic Founder Virus Escape Processes in HIV-1 Infection

2015 ◽  
Vol 89 (20) ◽  
pp. 10303-10318 ◽  
Author(s):  
Justine E. Sunshine ◽  
Brendan B. Larsen ◽  
Brandon Maust ◽  
Ellie Casey ◽  
Wenje Deng ◽  
...  
Keyword(s):  
T Cell ◽  
Viral Evolution ◽  
T Cell Responses ◽  
Fitness Cost ◽  
Viral Population ◽  
Cell Responses ◽  
Founder Virus ◽  
Ctl Escape ◽  
The Impact ◽  
Hiv 1

ABSTRACTTo understand the interplay between host cytotoxic T-lymphocyte (CTL) responses and the mechanisms by which HIV-1 evades them, we studied viral evolutionary patterns associated with host CTL responses in six linked transmission pairs. HIV-1 sequences corresponding to full-length p17 and p24gagwere generated by 454 pyrosequencing for all pairs near the time of transmission, and seroconverting partners were followed for a median of 847 days postinfection. T-cell responses were screened by gamma interferon/interleukin-2 (IFN-γ/IL-2) FluoroSpot using autologous peptide sets reflecting any Gag variant present in at least 5% of sequence reads in the individual's viral population. While we found little evidence for the occurrence of CTL reversions, CTL escape processes were found to be highly dynamic, with multiple epitope variants emerging simultaneously. We found a correlation between epitope entropy and the number of epitope variants per response (r= 0.43;P= 0.05). In cases in which multiple escape mutations developed within a targeted epitope, a variant with no fitness cost became fixed in the viral population. When multiple mutations within an epitope achieved fitness-balanced escape, these escape mutants were each maintained in the viral population. Additional mutations found to confer escape but undetected in viral populations incurred high fitness costs, suggesting that functional constraints limit the available sites tolerable to escape mutations. These results further our understanding of the impact of CTL escape and reversion from the founder virus in HIV infection and contribute to the identification of immunogenic Gag regions most vulnerable to a targeted T-cell attack.IMPORTANCERapid diversification of the viral population is a hallmark of HIV-1 infection, and understanding the selective forces driving the emergence of viral variants can provide critical insight into the interplay between host immune responses and viral evolution. We used deep sequencing to comprehensively follow viral evolution over time in six linked HIV transmission pairs. We then mapped T-cell responses to explore if mutations arose due to adaption to the host and found that escape processes were often highly dynamic, with multiple mutations arising within targeted epitopes. When we explored the impact of these mutations on replicative capacity, we found that dynamic escape processes only resolve with the selection of mutations that conferred escape with no fitness cost to the virus. These results provide further understanding of the complicated viral-host interactions that occur during early HIV-1 infection and may help inform the design of future vaccine immunogens.

scholarly journals How development affects evolution

2021 ◽  
Author(s):  
Mauricio González-Forero ◽  
Andy Gardner
Keyword(s):  
Niche Construction ◽  
Fitness Landscape ◽  
Stabilizing Selection ◽  
Mathematical Framework ◽  
Phenotypic Evolution ◽  
Landscape Development ◽  
Developmental Constraints ◽  
Evolutionary Pathway ◽  
Punctuated Equilibria ◽  
Adaptive Radiations

How development affects evolution. A mathematical framework that explicitly integrates development into evolution has recently been derived. Here we use this framework to analyse how development affects evolution. We show that, whilst selection pushes genetic and phenotypic evolution uphill on the fitness landscape, development determines the admissible evolutionary pathway, such that evolutionary outcomes occur at path peaks, which need not be peaks of the fitness landscape. Development can generate path peaks, triggering adaptive radiations, even on constant, single-peak landscapes. Phenotypic plasticity, niche construction, extra-genetic inheritance, and developmental bias variously alter the evolutionary path and hence the outcome. Selective development, whereby phenotype construction may point in the adaptive direction, may induce evolution either towards or away landscape peaks depending on the developmental constraints. Additionally, developmental propagation of phenotypic effects over age allows for the evolution of negative senescence. These results help explain empirical observations including punctuated equilibria, the paradox of stasis, the rarity of stabilizing selection, and negative senescence, and show that development has a major role in evolution.

scholarly journals A Pre-Vaccination Baseline of SARS-CoV-2 Genetic Surveillance and Diversity in the United States

Viruses ◽  
2022 ◽  
Vol 14 (1) ◽  
pp. 104
Author(s):  
Adam A. Capoferri ◽  
Wei Shao ◽  
Jon Spindler ◽  
John M. Coffin ◽  
Jason W. Rausch ◽  
...  
Keyword(s):  
United States ◽  
Genetic Diversity ◽  
Rna Virus ◽  
Viral Evolution ◽  
The United States ◽  
Virus Spread ◽  
Immune Pressure ◽  
Viral Genetic Diversity ◽  
Genetic Sampling ◽  
The U.S

COVID-19 vaccines were first administered on 15 December 2020, marking an important transition point for the spread of SARS-CoV-2 in the United States (U.S.). Prior to this point in time, the virus spread to an almost completely immunologically naïve population, whereas subsequently, vaccine-induced immune pressure and prior infections might be expected to influence viral evolution. Accordingly, we conducted a study to characterize the spread of SARS-CoV-2 in the U.S. pre-vaccination, investigate the depth and uniformity of genetic surveillance during this period, and measure and otherwise characterize changing viral genetic diversity, including by comparison with more recently emergent variants of concern (VOCs). In 2020, SARS-CoV-2 spread across the U.S. in three phases distinguishable by peaks in the numbers of infections and shifting geographical distributions. Virus was genetically sampled during this period at an overall rate of ~1.2%, though there was a substantial mismatch between case rates and genetic sampling nationwide. Viral genetic diversity tripled over this period but remained low in comparison to other widespread RNA virus pathogens, and although 54 amino acid changes were detected at frequencies exceeding 5%, linkage among them was not observed. Based on our collective observations, our analysis supports a targeted strategy for worldwide genetic surveillance as perhaps the most sensitive and efficient means of detecting new VOCs.

scholarly journals Development of intravenously administered synthetic RNA virus immunotherapy for the treatment of cancer

2021 ◽  
Author(s):  
Edward Kennedy ◽  
Agnieszka Denslow ◽  
Jacqueline Hewett ◽  
Lingxin Kong ◽  
Ana De Almeida ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Immune Cell ◽  
Rna Virus ◽  
Neutralizing Antibody ◽  
Repeated Administration ◽  
Oncolytic Viruses ◽  
Drug Candidates ◽  
Novel Approach ◽  
Coxsackievirus A21 ◽  
Anti Tumor Activity

Abstract Oncolytic viruses (OVs) are an emerging therapeutic approach for the treatment of cancer. Clinical benefit has been demonstrated for intratumoral administration, but the therapeutic effectiveness of intravenous delivery has been limited by neutralizing antibody responses against the virus. To circumvent this limitation, we developed Synthetic RNA viruses, a novel approach for intravenous and repeated administration of OVs, consisting of a viral RNA genome (vRNA) formulated within lipid nanoparticles. For two Synthetic RNA virus drug candidates, Seneca Valley virus (SVV) and Coxsackievirus A21 (CVA21), we demonstrate vRNA delivery, viral replication, spread, and lysis of tumor cells leading to potent anti-tumor efficacy, even in the presence of OV neutralizing antibodies in the bloodstream. Synthetic-SVV replication in tumors promoted immune cell infiltration and enhanced anti-tumor activity in combination with anti-PD-1 checkpoint inhibitor. Altogether, the Synthetic RNA virus platform provides an innovative approach that enables repeat intravenous administration of viral immunotherapy.

scholarly journals Evolution of gene regulatory networks by means of selection and random genetic drift

2018 ◽  
Author(s):  
Antonios Kioukis ◽  
Pavlos Pavlidis
Keyword(s):  
Natural Selection ◽  
Positive Selection ◽  
Genetic Drift ◽  
Regulatory Networks ◽  
Fitness Landscape ◽  
Random Genetic Drift ◽  
Maturation Period ◽  
Evolutionary Forces ◽  
Gene Regulatory

The evolution of a population by means of genetic drift and natural selection operating on a gene regulatory network (GRN) of an individual has not been scrutinized in depth. Thus, the relative importance of various evolutionary forces and processes on shaping genetic variability in GRNs is understudied. Furthermore, it is not known if existing tools that identify recent and strong positive selection from genomic sequences, in simple models of evolution, can detect recent positive selection when it operates on GRNs. Here, we propose a simulation framework, called EvoNET, that simulates forward-in-time the evolution of GRNs in a population. Since the population size is finite, random genetic drift is explicitly applied. The fitness of a mutation is not constant, but we evaluate the fitness of each individual by measuring its genetic distance from an optimal genotype. Mutations and recombination may take place from generation to generation, modifying the genotypic composition of the population. Each individual goes through a maturation period, where its GRN reaches equilibrium. At the next step, individuals compete to produce the next generation. As time progresses, the beneficial genotypes push the population higher in the fitness landscape. We examine properties of the GRN evolution such as robustness against the deleterious effect of mutations and the role of genetic drift. We confirm classical results from Andreas Wagner’s work that GRNs show robustness against mutations and we provide new results regarding the interplay between random genetic drift and natural selection.

Heterozygote advantage and the evolution of a dominant diploid phase.

Genetics ◽  
1992 ◽  
Vol 132 (4) ◽  
pp. 1195-1198 ◽  
Author(s):  
D B Goldstein
Keyword(s):  
Life Cycle ◽  
Sexual Reproduction ◽  
Genetic Factor ◽  
Higher Plants ◽  
Heterozygote Advantage ◽  
Seed Plants ◽  
Sexual Species ◽  
Evolutionary Forces ◽  
Eukaryotic Species ◽  
Selection For

Abstract The life cycle of eukaryotic, sexual species is divided into haploid and diploid phases. In multicellular animals and seed plants, the diploid phase is dominant, and the haploid phase is reduced to one, or a very few cells, which are dependent on the diploid form. In other eukaryotic species, however, the haploid phase may dominate or the phases may be equally developed. Even though an alternation between haploid and diploid forms is fundamental to sexual reproduction in eukaryotes, relatively little is known about the evolutionary forces that influence the dominance of haploidy or diploidy. An obvious genetic factor that might result in selection for a dominant diploid phase is heterozygote advantage, since only the diploid phase can be heterozygous. In this paper, I analyze a model designed to determine whether heterozygote advantage could lead to the evolution of a dominant diploid phase. The main result is that heterozygote advantage can lead to an increase in the dominance of the diploid phase, but only if the diploid phase is already sufficiently dominant. Because the diploid phase is unlikely to be increased in organisms that are primarily haploid, I conclude that heterozygote advantage is not a sufficient explanation of the dominance of the diploid phase in higher plants and animals.

scholarly journals Differences in the Binding Affinity of an HIV-1 V2 Apex-Specific Antibody for the SIVsmm/macEnvelope Glycoprotein Uncouple Antibody-Dependent Cellular Cytotoxicity from Neutralization

mBio ◽  
2019 ◽  
Vol 10 (4) ◽  
Author(s):  
Benjamin von Bredow ◽  
Raiees Andrabi ◽  
Michael Grunst ◽  
Andres G. Grandea ◽  
Khoa Le ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Specific Antibody ◽  
Neutralizing Antibody ◽  
Glycosylation Site ◽  
Antibody Binding ◽  
Cellular Cytotoxicity ◽  
Antibody Dependent Cellular Cytotoxicity ◽  
Broadly Neutralizing Antibody ◽  
Infected Cells ◽  
Hiv 1

ABSTRACTAs a consequence of their independent evolutionary origins in apes and Old World monkeys, human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency viruses of the SIVsmm/maclineage express phylogenetically and antigenically distinct envelope glycoproteins. Thus, HIV-1 Env-specific antibodies do not typically cross-react with the Env proteins of SIVsmm/macisolates. Here we show that PGT145, a broadly neutralizing antibody to a quaternary epitope at the V2 apex of HIV-1 Env, directs the lysis of SIVsmm/mac-infected cells by antibody-dependent cellular cytotoxicity (ADCC) but does not neutralize SIVsmm/macinfectivity. Amino acid substitutions in the V2 loop of SIVmac239 corresponding to the epitope for PGT145 in HIV-1 Env modulate sensitivity to this antibody. Whereas a substitution in a conserved N-linked glycosylation site (N171Q) eliminates sensitivity to ADCC, a lysine-to-serine substitution in this region (K180S) increases ADCC and renders the virus susceptible to neutralization. These differences in function correlate with an increase in the affinity of PGT145 binding to Env on the surface of virus-infected cells and to soluble Env trimers. To our knowledge, this represents the first instance of an HIV-1 Env-specific antibody that cross-reacts with SIVsmm/macEnv and illustrates how differences in antibody binding affinity for Env can differentiate sensitivity to ADCC from neutralization.IMPORTANCEHere we show that PGT145, a potent broadly neutralizing antibody to HIV-1, directs the lysis of SIV-infected cells by antibody-dependent cellular cytotoxicity but does not neutralize SIV infectivity. This represents the first instance of cross-reactivity of an HIV-1 Env-specific antibody with SIVsmm/macEnv and reveals that antibody binding affinity can differentiate sensitivity to ADCC from neutralization.

scholarly journals Selection for thermostability can lead to the emergence of mutational robustness in an RNA virus

2010 ◽  
Vol 23 (11) ◽  
pp. 2453-2460 ◽  
Author(s):  
P. DOMINGO-CALAP ◽  
M. PEREIRA-GÓMEZ ◽  
R. SANJUÁN
Keyword(s):  
Rna Virus ◽  
Mutational Robustness ◽  
Selection For
Sign in / Sign up

Export Citation Format

Share Document