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 A de novo approach to inferring within-host fitness effects during untreated HIV-1 infection

2019 ◽  
Author(s):  
Christopher J. R. Illingworth ◽  
Jayna Raghwani ◽  
David Serwadda ◽  
Nelson K. Sewankambo ◽  
Merlin L. Robb ◽  
...  
Keyword(s):  
Positive Selection ◽  
Sequence Data ◽  
Viral Population ◽  
Clonal Interference ◽  
Neutralising Antibodies ◽  
Host Diversity ◽  
Fitness Effects ◽  
Ctl Escape ◽  
Hiv 1

AbstractIn the absence of effective antiviral therapy, HIV-1 evolves in response to the within-host environment, of which the immune system is an important aspect. During the earliest stages of infection, this process of evolution is very rapid, driven by a small number of CTL escape mechanisms. As the infection progresses, immune escape variants evolve under reduced magnitudes of selection, while competition between an increasing number of polymorphic alleles (i.e., clonal interference) makes it difficult to quantify the magnitude of selection acting upon specific variant alleles. To tackle this complex problem, we developed a novel multi-locus inference method to evaluate the role of selection during the chronic stage of within-host infection. We applied this method to targeted sequence data from the p24 and gp41 regions of HIV-1 collected from 34 patients with long-term untreated HIV-1 infection. We identify a broad distribution of beneficial fitness effects during infection, with a small number of variants evolving under strong selection and very many variants evolving under weaker selection. The uniquely large number of infections analysed granted a previously unparalleled statistical power to identify loci at which selection could be inferred to act with statistical confidence. Our model makes no prior assumptions about the nature of alleles under selection, such that any synonymous or non-synonymous variant may be inferred to evolve under selection. However, the majority of variants inferred with confidence to be under selection were non-synonymous in nature, and in nearly all cases were associated with either CTL escape in p24 or neutralising antibody escape in gp41. Sites inferred to be under selection in multiple hosts have high within-host and between-host diversity albeit not all sites with high between-host diversity were inferred to be under selection at the within-host level. Our identification of selection at sites associated with resistance to broadly neutralising antibodies (bNAbs) highlights the need to fully understand the role of selection in untreated individuals when designing bNAb based therapies.Author SummaryDuring the within-host evolution of HIV-1, the diversity of the viral population increases, with many beneficial variants competing against each other. This competition, known as clonal interference, makes the identification of variants under positive selection a challenging task. We here apply a novel method for the inference of selection to targeted within-host sequence data describing changes in the p24 and gp41 genes during HIV-1 infection in 34 patients. Our method adopts a parsimonious approach, assigning selection to the smallest number of variants necessary to explain the evolution of the system. The large size of our dataset allows for the confident identification of variants under selection, alleles at certain loci being repeatedly inferred as under selection within multiple individuals. While early CTL escape mutations have been identified to evolve under strong positive selection, we identify a distribution of beneficial fitness effects in which a large number of mutations are under weak selection. Variants that were confidently identified under selection were primarily found to be associated with either CTL escape in p24 or neutralising antibody escape in gp41, including sites associated with escape from broadly neutralising antibodies. We find that the most frequently selected loci have high diversity both within-host and at the between-host level.

scholarly journals Signal Pre-Selection for Monitoring and Prediction of Vehicle Powertrain Component Aging

2019 ◽  
Vol 18 (6) ◽  
pp. 519-524
Author(s):  
A. Udo Sass ◽  
E. Esatbeyoglu ◽  
T. Iwwerks
Keyword(s):  
Aging Process ◽  
Time Series Data ◽  
Machine Learning Algorithms ◽  
Predictive Maintenance ◽  
Series Data ◽  
Time Intervals ◽  
Vehicle Data ◽  
Control Units ◽  
Interpretable Model ◽  
Selection For

Predictive maintenance has become important for avoiding unplanned downtime of modern vehicles. With increasing functionality the exchanged data between Electronic Control Units (ECU) grows simultaneously rapidly. A large number of in-vehicle signals are provided for monitoring an aging process. Various components of a vehicle age due to their usage. This component aging is only visible in a certain number of in-vehicle signals. In this work, we present a signal selection method for in-vehicle signals in order to determine relevant signals to monitor and predict powertrain component aging of vehicles. Our application considers the aging of powertrain components with respect to clogging of structural components. We measure the component aging process in certain time intervals. Owing to this, unevenly spaced time series data is preprocessed to generate comparable in-vehicle data. First, we aggregate the data in certain intervals. Thus, the dynamic in-vehicle database is reduced which enables us to analyze the signals more efficiently. Secondly, we implement machine learning algorithms to generate a digital model of the measured aging process. With the help of Local Interpretable Model-Agnostic Explanations (LIME) the model gets interpretable. This allows us to extract the most relevant signals and to reduce the amount of processed data. Our results show that a certain number of in-vehicle signals are sufficient for predicting the aging process of the considered structural component. Consequently, our approach allows to reduce data transmission of in-vehicle signals with the goal of predictive maintenance.

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 Evolution of the Envelope Glycoprotein of HIV-1 Clade B toward Higher Infectious Properties over the Course of the Epidemic

2018 ◽  
Vol 93 (6) ◽  
Author(s):  
Mélanie Bouvin-Pley ◽  
Maxime Beretta ◽  
Alain Moreau ◽  
Emmanuelle Roch ◽  
Asma Essat ◽  
...  
Keyword(s):  
Functional Properties ◽  
Envelope Glycoprotein ◽  
Neutralizing Antibodies ◽  
Viral Fitness ◽  
Cell Entry ◽  
Viral Population ◽  
Target Cells ◽  
Subtype B ◽  
Antigenic Evolution ◽  
Hiv 1

ABSTRACT We showed previously that during the HIV/AIDS epidemic, the envelope glycoprotein (Env) of HIV-1, and in particular, the gp120 subunit, evolved toward an increased resistance to neutralizing antibodies at a population level. Here, we considered whether the antigenic evolution of the HIV-1 Env is associated with modifications of its functional properties, focusing on cell entry efficacy and interactions with the receptor and coreceptors. We tested the infectivity of a panel of Env-pseudotyped viruses derived from patients infected by subtype B viruses at three periods of the epidemic (1987 to 1991, 1996 to 2000, and 2006 to 2010). Pseudotyped viruses harboring Env from patients infected during the most recent period were approximately 10-fold more infectious in cell culture than those from patients infected at the beginning of the epidemic. This was associated with faster viral entry kinetics: contemporary viruses entered target cells approximately twice as fast as historical viruses. Contemporary viruses were also twice as resistant as historical viruses to the fusion inhibitor enfuvirtide. Resistance to enfuvirtide correlated with a resistance to CCR5 antagonists, suggesting that contemporary viruses expanded their CCR5 usage efficiency. Viruses were equally captured by DC-SIGN, but after binding to DC-SIGN, contemporary viruses infected target cells more efficiently than historical viruses. Thus, we report evidence that the infectious properties of the envelope glycoprotein of HIV-1 increased during the course of the epidemic. It is plausible that these changes affected viral fitness during the transmission process and might have contributed to an increasing virulence of HIV-1. IMPORTANCE Following primary infection by HIV-1, neutralizing antibodies (NAbs) exert selective pressure on the HIV-1 envelope glycoprotein (Env), driving the evolution of the viral population. Previous studies suggested that, as a consequence, Env has evolved at the HIV species level since the start of the epidemic so as to display greater resistance to NAbs. Here, we investigated whether the antigenic evolution of the HIV-1 Env is associated with modifications of its functional properties, focusing on cell entry efficacy and interactions with the receptor and coreceptors. Our data provide evidence that the infectious properties of the HIV-1 Env increased during the course of the epidemic. These changes may have contributed to increasing virulence of HIV-1 and an optimization of transmission between individuals.

scholarly journals An Approximate Markov Model for the Wright-Fisher Diffusion

2015 ◽  
Author(s):  
Anna Ferrer-Admetlla ◽  
Christoph Leuenberger ◽  
Jeffrey D Jensen ◽  
Daniel Wegmann
Keyword(s):  
Time Series Data ◽  
Diffusion Processes ◽  
Viral Population ◽  
Series Data ◽  
Recent Experimental Data ◽  
Data Sets ◽  
Multiple Time ◽  
Sequencing Errors ◽  
Additional Information ◽  
Multiple Time Points

The joint and accurate inference of selection and demography from genetic data is considered a particularly challenging question in population genetics, since both process may lead to very similar patterns of genetic diversity. However, additional information for disentangling these effects may be obtained by observing changes in allele frequencies over multiple time points. Such data is common in experimental evolution studies, as well as in the comparison of ancient and contemporary samples. Leveraging this information, however, has been computationally challenging, particularly when considering multi-locus data sets. To overcome these issues, we introduce a novel, discrete approximation for diffusion processes, termed \textit{mean transition time approximation}, which preserves the long-term behavior of the underlying continuous diffusion process. We then derive this approximation for the particular case of inferring selection and demography from time series data under the classic Wright-Fisher model and demonstrate that our approximation is well suited to describe allele trajectories through time, even when only a few states are used. We then develop a Bayesian inference approach to jointly infer the population size and locus-specific selection coefficients with high accuracy, and further extend this model to also infer the rates of sequencing errors and mutations. We finally apply our approach to recent experimental data on the evolution of drug resistance in Influenza virus, identifying likely targets of selection and finding evidence for much larger viral population sizes than previously reported.

scholarly journals Infant Transmitted/Founder HIV-1 Viruses from Peripartum Transmission are Neutralization Resistant to Paired Maternal Plasma

2017 ◽  
Author(s):  
Amit Kumar ◽  
Claire E. P. Smith ◽  
Elena E. Giorgi ◽  
Joshua Eudailey ◽  
David R. Martinez ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Maternal Plasma ◽  
Pediatric Hiv ◽  
Viral Population ◽  
Single Genome Amplification ◽  
Genome Amplification ◽  
Implementation Challenges ◽  
Amplification Method ◽  
Single Genome ◽  
Hiv 1

AbstractDespite extensive genetic diversity of HIV-1 in chronic infection, infant HIV-1 infection involves selective transmission of a single or few maternal virus variants. These transmitted/founder (T/F) variants are of particular interest, as a maternal or infant HIV vaccine should raise envelope (Env)-specific IgG responses capable of blocking this group of viruses. However, the maternal or infant factors that contribute to selection of infant T/F viruses are not well understood. In this study, we isolated HIV-1envgenes by single genome amplification from 16 mother-infant transmitting pairs from the U.S. pre-antiretroviral era Women Infant Transmission Study (WITS). Infant T/F and representative maternal non-transmitted Env variants from plasma were identified and used to generate pseudoviruses for paired maternal plasma neutralization sensitivity analysis. Eighteen out of 21 (85%) infant T/F Env pseudoviruses were neutralization resistant to paired maternal plasma. Yet, all infant T/F viruses were neutralization sensitive to a panel of HIV-1 broadly neutralizing antibodies and variably sensitive to heterologous plasma neutralizing antibodies. Moreover, infant T/F pseudoviruses were overall more neutralization resistant compared to maternal non-transmitted plasma variants (p=0.012). Altogether, our findings suggest that autologous neutralization of circulating viruses by maternal plasma antibodies select for neutralization-resistant viruses that initiate peripartum transmission, raising the spector that enhancement of this response at the end of pregnancy could further reduce infant HIV infection risk.Author SummaryMother to child transmission (MTCT) of HIV-1 can occur during pregnancy (in utero), at the time of delivery (peripartum) or by breastfeeding (postpartum). With the availability of anti-retroviral therapy (ART), rate of MTCT of HIV-1 have been significantly lowered. However, significant implementation challenges remains in resource-poor areas, making it difficult to eliminate pediatric HIV. An improved understanding of the viral population (escape variants from autologous neutralizing antibodies) that lead to infection of infants at time of transmission will help in designing immune interventions to reduce vertical HIV-1 transmission. Here, we selected 16 HIV-1-infected mother-infant pairs from WITS cohort (from pre anti-retroviral era), where infants became infected peripartum. HIV-1envgene sequences were obtained by the single genome amplification method. The sensitivity of these infant Env pseudoviruses against paired maternal plasma and a panel of broadly neutralizing monoclonal antibodies (bNAbs) was analyzed. We demonstrated that the infant T/F viruses were more resistant against maternal plasma than non-transmitted maternal variants, but sensitive to most (bNAbs). Signature sequence analysis of infant T/F and non-transmitted maternal variants revealed the potential importance of V3 and MPER region for resistance against to paired maternal plasma. These findings provide insights for the design of maternal immunization strategies to enhance neutralizing antibodies that target V3 region of autologous virus populations, which could work synergistically with maternal ARVs to further reduce the rate of peripartum HIV-1 transmission.

Graphical Exploratory Data Analysis for Categorical Longitudinal and Time Series Data

2013 ◽  
Author(s):  
Stephen J. Tueller ◽  
Richard A. Van Dorn ◽  
Georgiy Bobashev ◽  
Barry Eggleston
Keyword(s):  
Time Series ◽  
Data Analysis ◽  
Exploratory Data Analysis ◽  
Time Series Data ◽  
Series Data ◽  
Exploratory Data
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