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At least 145 records · Page 8Linked to original sources

PubMed2002

Experimental genomic evolution: extensive compensation for loss of DNA ligase activity in a virus.

Deletion of the viral ligase gene drastically reduced the fitness of bacteriophage T7 on a ligase-deficient host. Viral evolution recovered much of this fitness during long-term passage, but the final fitness remained below that of the intact virus. Compensatory changes occurred chiefly in genes involved in DNA metabolism: the viral endonuclease, helicase, and DNA polymerase. Two other compensatory changes of unknown function also occurred. Using a method to distinguish compensatory mutations from other beneficial mutations, five additional substitutions from the recovery were shown to enhance adaptation to culture conditions and were not compensatory for the deletion. In contrast to the few previous studies of viral recovery from deletions, the compensatory changes in T7 did not restore the deletion or duplicate major regions of the genome. The ability of this deleted genome to recover much of the lost fitness via mutations in its remaining genes reveals a considerable evolutionary potential to modify the interactions of its elements in maintaining an essential set of functions.

Adaptation, Physiological↗

PubMed2001

Multiplicity of infection and the evolution of hybrid incompatibility in segmented viruses.

Some viral genomes are divided into segments. When multiple viruses infect a single cell, progeny form by reassorted mixtures of genomic segments. Hybrid incompatibilities arise when a progeny virus has incompatible segments from different parental viruses. Hybrid incompatibility has been observed in influenza and in the multiparticle plant virus Dianthovirus. Hybrid incompatibility provides an opportunity to study rates of viral evolution, divergence and speciation, and the extent of epistatic interactions among components of the viral genome. This paper presents mathematical and computer simulation models to study hybrid incompatibility between diverging strains. The models identify multiplicity of infection as a key factor. When many viral particles infect each host cell, the effective ploidy of the genetic system is high. High ploidy dilutes the contribution of each locus to the phenotype, weakening the selective intensity on each locus. Weaker selection on variant alleles allows the population to maintain greater genetic diversity and to be more easily perturbed by stochastic fluctuations. Greater diversity and stochastic fluctuations explore more widely the space of epistatic interactions, causing more frequent shifts among favoured combinations of alleles. Variable ploidy of viral genetics differs from standard Mendelian genetics.

Computer Simulation↗

PubMed2001

An in vitro DNA virus for in vitro protein evolution.

In vitro virus is a molecular construct for in vitro protein evolution, which requires some mechanism to link phenotype to genotype. The first in vitro virus was realized by bonding a nascent protein with its coding mRNA via puromycin in in vitro translation. We report a new construct of in vitro DNA virus. The virion was a covalent cDNA-protein fusion, and virion formation did not require any modification of mRNA. Due to intactness of mRNA, this type of in vitro DNA virus will take the next step toward in vitro autonomous evolution, just like in vivo viral evolution in a cellstat.

DNA Primers↗

PubMed2025

SARS-CoV-2 genomic diversity and within-host evolution in individuals with persistent infection in the UK: an observational, longitudinal, population-based surveillance study.

BACKGROUND: Persistent SARS-CoV-2 infections in hospitalised immunocompromised individuals are known to facilitate accelerated within-host viral evolution, potentially contributing to the emergence of highly divergent variants. However, little is known about the evolutionary dynamics and transmission risks of persistent infections in the general population. We aimed to characterise the within-host evolution of SARS-CoV-2 during persistent infections identified through a large community surveillance study. METHODS: We used data from the Office for National Statistics COVID-19 Infection Survey (ONS-CIS), a large-scale, longitudinal, population-based surveillance study conducted in the UK from April, 2020, to March, 2023. For this analysis, we focused on infections with high viral load (cycle threshold ≤30) and available genome sequences, from seven major SARS-CoV-2 lineages (alpha, delta, BA.1, BA.2, BA.4, BA.5, and XBB). ONS-CIS participants were randomly selected from the general population and tested regularly by RT-PCR, regardless of symptoms. We defined persistent infections as those with sustained or rebounding high viral RNA titres for 26 days or longer. We examined associated host characteristics and used raw sequence data to identify de novo mutations and estimate within-host synonymous and non-synonymous evolutionary rates across the SARS-CoV-2 genome. FINDINGS: Between Nov 2, 2020, and March 21, 2023, we identified 576 persistent infections with at least two sequences, including 11 alpha, 106 delta, 102 BA.1, 204 BA.2, 16 BA.4, 133 BA.5, and 4 XBB. Persistent infections were more common in males than females (p<0·0001) and individuals older than 60 years (p=0·0027). The median within-host genome-wide evolutionary rate was 7·9 × 10-4 substitutions per site per year (IQR 7·0-9·0 × 10-4), with high inter-individual variability driven largely by non-synonymous mutations, particularly in the N-terminal and receptor-binding domains of the spike protein. Longer infection duration was associated with higher evolutionary rates, while no associations were found with age, sex, vaccination status, previous infection, or virus lineage. We found no clear evidence of transmission beyond the first month of infection in any of the 84 persistent infections lasting 56 days or longer. In total, we identified 379 recurrent mutations, including many with known or predicted negative fitness effects and low prevalence at the population level, as well as de novo reversions to the Wuhan-Hu-1 reference sequence, which were likely under positive selection within those individuals. INTERPRETATION: This study highlights the heterogeneous nature of within-host SARS-CoV-2 evolution in individuals with persistent infection in the community. Notably, a small subset of persistent infections with high viral loads underwent accelerated viral evolution or recurrently acquired hallmark mutations found in novel variants. In addition, onward transmission from a persistent infection during the later stages of infection is likely to be rare. These insights have important implications for prioritising genomic surveillance and managing patients with persistent infections. FUNDING: Department of Health and Social Care.

Humans↗

PubMed2027

Optimized Amplicon Strategy for Long-Read Sequencing of the Chikungunya Virus Genome.

Chikungunya virus (CHIKV) is a positive-sense RNA alphavirus transmitted to humans primarily by Aedes aegypti and Aedes albopictus mosquitoes. Its global circulation and significant public health impact underscore the need to better understand the molecular mechanisms driving CHIKV pathogenesis and transmission. Although robust molecular biology methods exist for CHIKV genome sequencing, a major limitation for surveillance and research is the inability to determine whether two nucleotide variations co-occur within the same viral genome when they are separated beyond the span of typical short-read designs. Here, we describe an optimized approach for processing CHIKV RNA samples that generates large amplicons suitable for long-read nanopore sequencing. This protocol enables amplification of the complete CHIKV genome in only two or three amplicons and facilitates detection of co-occurring nucleotide variations across 4-7.5 kb within the same molecule, thereby simplifying sequencing workflows and improving resolution in studies of viral evolution.

Chikungunya virus↗

PubMed2006

Genetic analyses reveal structured HIV-1 populations in serially sampled T lymphocytes of patients receiving HAART.

HIV-1 infection and compartmentalization in diverse leukocyte targets significantly contribute to viral persistence during suppressive highly active antiretroviral therapy (HAART). Longitudinal analyses were performed on envelope sequences of HIV-1 populations from plasma, CD4+ and CD8+ T lymphocytes in 14 patients receiving HAART and 1 therapy-naive individual. Phylogenetic reconstructions and analysis of molecular variance revealed that HIV-1 populations in CD4+ and CD8+ T cells remained compartmentalized over time in most individuals. Analyses of viral genetic variation demonstrated that, despite compartmentalization remaining over time, viral subpopulations tended not to persist and evolve but instead broke down and became reconstituted by new founder viruses. Due to the profound impact of HAART on viral evolution, it was difficult to discern whether these dynamics were ongoing during treatment or predominantly established prior to the commencement of therapy. The genetic structure and viral founder effects observed in serially sampled T lymphocyte populations supported a scenario of metapopulation dynamics in the tissue(s) where different leukocytes become infected, a factor likely to contribute to the highly variable way that drug resistance evolves in different individuals during HAART.

Antiretroviral Therapy, Highly Active↗

PubMed2003

Limitations on geminivirus genome size imposed by plasmodesmata and virus-encoded movement protein: insights into DNA trafficking.

Animals and plants evolved systems to permit non-cell-autonomous trafficking of RNA, whereas DNA plays a cell-autonomous role. In plants, plasmodesmata serve as the conduit for this phenomenon, and viruses have evolved to use this pathway for the spread of infectious nucleic acids. In this study, a plant DNA virus was used to explore the constraints imposed on the movement of DNA through this endogenous RNA trafficking pathway. The combined properties of the geminivirus-encoded movement protein and plasmodesmata were shown to impose a strict limitation on the size of the viral genome at the level of cell-to-cell movement. Size-increased viral genome components underwent homologous and nonhomologous recombination to overcome this strict limitation. Our results provide insights into the genetic mechanisms that underlie viral evolution and provide a likely explanation for why relatively few types of plant DNA viruses have evolved: they would have had to overcome the constraints imposed by an endogenous system operating to ensure that DNA acts in a cell-autonomous manner.

Cloning, Molecular↗

PubMed2006

Evolutionary basis of codon usage and nucleotide composition bias in vertebrate DNA viruses.

Understanding the extent and causes of biases in codon usage and nucleotide composition is essential to the study of viral evolution, particularly the interplay between viruses and host cells or immune responses. To understand the common features and differences among viruses we analyzed the genomic characteristics of a representative collection of all sequenced vertebrate-infecting DNA viruses. This revealed that patterns of codon usage bias are strongly correlated with overall genomic GC content, suggesting that genome-wide mutational pressure, rather than natural selection for specific coding triplets, is the main determinant of codon usage. Further, we observed a striking difference in CpG content between DNA viruses with large and small genomes. While the majority of large genome viruses show the expected frequency of CpG, most small genome viruses had CpG contents far below expected values. The exceptions to this generalization, the large gammaherpesviruses and iridoviruses and the small dependoviruses, have sufficiently different life-cycle characteristics that they may help reveal some of the factors shaping the evolution of CpG usage in viruses.

Animals↗

PubMed2005

A simple and rapid approach for screening of SARS-coronavirus genotypes: an evaluation study.

BACKGROUND: The Severe Acute Respiratory Syndrome (SARS) was a newly emerged infectious disease which caused a global epidemic in 2002-2003. Sequence analysis of SARS-coronavirus isolates revealed that specific genotypes predominated at different periods of the epidemic. This information can be used as a footprint for tracing the epidemiology of infections and monitor viral evolution. However, direct sequencing analysis of a large number of clinical samples is cumbersome and time consuming. We present here a simple and rapid assay for the screening of SARS-coronavirus genotypes based on the use of fluorogenic oligonucleotide probes for allelic discrimination. METHODS: Thirty SARS patients were recruited. Allelic discrimination assays were developed based on the use of fluorogenic oligonucleotide probes (TaqMan). Genotyping of the SARS-coronavirus isolates obtained from these patients were carried out by the allelic discrimination assays and confirmed by direct sequencing. RESULTS: Genotyping based on the allelic discrimination assays were fully concordant with direct sequencing. All of the 30 SARS-coronavirus genotypes studied were characteristic of genotypes previously documented to be associated with the latter part of the epidemic. Seven of the isolates contained a previously reported major deletion but in patients not epidemiologically related to the previously studied cohort. CONCLUSION: We have developed a simple and accurate method for the characterization and screening of SARS-coronavirus genotypes. It is a promising tool for the study of epidemiological relationships between documented cases during an outbreak.

Alleles↗

PubMed2005

Wave-like spread of Ebola Zaire.

In the past decade the Zaire strain of Ebola virus (ZEBOV) has emerged repeatedly into human populations in central Africa and caused massive die-offs of gorillas and chimpanzees. We tested the view that emergence events are independent and caused by ZEBOV variants that have been long resident at each locality. Phylogenetic analyses place the earliest known outbreak at Yambuku, Democratic Republic of Congo, very near to the root of the ZEBOV tree, suggesting that viruses causing all other known outbreaks evolved from a Yambuku-like virus after 1976. The tendency for earlier outbreaks to be directly ancestral to later outbreaks suggests that outbreaks are epidemiologically linked and may have occurred at the front of an advancing wave. While the ladder-like phylogenetic structure could also bear the signature of positive selection, our statistical power is too weak to reach a conclusion in this regard. Distances among outbreaks indicate a spread rate of about 50 km per year that remains consistent across spatial scales. Viral evolution is clocklike, and sequences show a high level of small-scale spatial structure. Genetic similarity decays with distance at roughly the same rate at all spatial scales. Our analyses suggest that ZEBOV has recently spread across the region rather than being long persistent at each outbreak locality. Controlling the impact of Ebola on wild apes and human populations may be more feasible than previously recognized.

Animals↗

PubMed2004

MinPD: distance-based phylogenetic analysis and recombination detection of serially-sampled HIV quasispecies.

A new computational method to study within-host viral evolution is explored to better understand the evolution and pathogenesis of viruses. Traditional phylogenetic tree methods are better suited to study relationships between contemporaneous species, which appear as leaves of a phylogenetic tree. However, viral sequences are often sampled serially from a single host. Consequently, data may be available at the leaves as well as the internal nodes of a phylogenetic tree. Recombination may further complicate the analysis. Such relationships are not easily expressed by traditional phylogenetic methods. We propose a new algorithm, called MinPD, based on minimum pairwise distances. Our algorithm uses multiple distance matrices and correlation rules to output a MinPD tree or network. We test our algorithm using extensive simmulations and apply it to a set of HIV sequence data isolated from one patient over a period of ten years. The proposed visualization of the phylogenetic tree\network further enhances the benefits of our methods.

Algorithms↗

PubMed2026

Emergence of two novel HIV-1 Circulating Recombinant Forms (CRF190_0708 and CRF191_0708): molecular characterization and clinical insights from a five-year study in Yunnan, China.

BACKGROUND: To characterize HIV-1 molecular epidemiology and identify novel circulating recombinant forms (CRFs) among antiretroviral therapy (ART)-naïve heterosexuals in Yunnan, China, and evaluate their clinical impact. METHODS: This study examined 636 HIV-1 pol sequences to analyze genetic diversity, pretreatment drug resistance (PDR), and transmission networks. Near full-length genomes were obtained to identify and characterize novel recombinants, with their evolutionary history inferred by Bayesian analysis. Co-receptor tropism was predicted, and the five-year clinical outcomes (including immune reconstitution and virologic response) of patients infected with the novel CRFs were compared. RESULTS: The most prevalent type identified was CRF08_BC, accounting for 50.16% of cases. The prevalence of drug resistance was 5.97% (38/636), with the K103N mutation being the most common. An analysis of transmission networks revealed that 52.2% (272/521) of clusters were associated with CRF07_BC and CRF08_BC. Two novel second-generation CRFs were identified: CRF190_0708, with an estimated time to the most recent common ancestor (tMRCA) of 1998.9, and CRF191_0708, with a more recent tMRCA ranging from 2009.5 to 2011.6. During the five-year follow-up period, viral rebound was observed in 7 patients in the CRF190_0708 group and in 1 patient in the CRF191_0708 group. Drug-resistance mutations (M184V and K103N) were detected in a subset of rebound cases in the CRF190_0708 group. CONCLUSIONS: This study identifies two novel HIV-1 recombinants, CRF190_0708 and CRF191_0708, highlighting ongoing viral evolution in Yunnan. Preliminary findings suggest possible clinical differences, warranting further investigation. Continued molecular surveillance is needed. TRIAL REGISTRATION: The clinical study was registered at ClinicalTrials.gov under the identifier NCT03852849. The date of registration was March 22, 2019.

Adult↗

PubMed1995

The evolution of small DNA viruses of eukaryotes: past and present considerations.

Historically, viral evolution has often been considered from the perspective of the ability of the virus to maintain viral pathogenic fitness by causing disease. A predator-prey model has been successfully applied to explain genetically variable quasi-species of viruses, such as influenza virus and human immunodeficiency virus (HIV), which evolve much faster rates than the host. In contrast, small DNA viruses (polyomaviruses, papillomaviruses, and parvoviruses) are species specific but are stable genetically, and appear to have co-evolved with their host species. Genetic stability is attributable primarily to the ability to establish and maintain a benign persistent state in vivo and not to the host DNA proofreading mechanisms. The persistent state often involves a cell cycle-regulated episomal state and a tight linkage of DNA amplification mechanisms to cellular differentiation. This linkage requires conserved features among viral regulatory proteins, with characteristic host-interactive domains needed to recruit and utilize host machinery, thus imposing mechanistic constrains on possible evolutionary options. Sequence similarities within these domains are seen amongst all small mammalian DNA viruses and most of the parvo-like viruses, including those that span the entire spectrum of evolution of organisms from E. coli to humans that replicate via a rolling circle-like mechanism among the entire spectrum of organisms throughout evolution from E. coli to humans. To achieve benign inapparent viral persistence, small DNA viruses are proposed to circumvent the host acute phase reaction (characterized by minimal inflammation) by mechanisms that are evolutionarily adapted to the immune system and the related cytokine communication networks. A striking example of this is the relationship of hymenoptera to polydnaviruses, in which the crucial to the recognition of self, development, and maintenance of genetic identity of both the host and virus. These observations in aggregate suggest that viral replicons are not recent "escapies" of host replication, but rather provide relentless pressure in driving the evolution of the host through cospeciation.

Adaptation, Physiological↗

PubMed2003

Multiple viral genetic analyses detect low-level human immunodeficiency virus type 1 replication during effective highly active antiretroviral therapy.

To evaluate human immunodeficiency virus type 1 (HIV-1) replication and selection of drug-resistant viruses during seemingly effective highly active antiretroviral therapy (HAART), multiple HIV-1 env and pol sequences were analyzed and viral DNA levels were quantified from nucleoside analog-experienced children prior to and during a median of 5.1 (range, 1.8 to 6.4) years of HAART. Viral replication was detected at different rates, with apparently increasing sensitivity: 1 of 10 by phylogenetic analysis; 2 of 10 by viral evolution with increasing genetic distances from the most recent common ancestor (MRCA) of infection; 3 of 10 by selection of drug-resistant mutants; and 6 of 10 by maintenance of genetic distances from the MRCA. When four- or five-drug antiretroviral regimens were given to these children, persistent plasma viral rebound did not occur despite the accumulation of highly drug-resistant genotypes. Among the four children without genetic evidence of viral replication, a statistically significant decrease in the genetic distance to the MRCA was detected in three, indicating the persistence of a greater number of early compared to recent viruses, and their HIV-1 DNA decreased by > or =0.9 log(10), resulting in lower absolute DNA levels (P = 0.007). This study demonstrates the variable rates of viral replication when HAART has suppressed plasma HIV-1 RNA for years to a median of <50 copies/ml and that combinations of four or five antiretroviral drugs suppress viral replication even after short-term virologic failure of three-drug HAART and despite ongoing accumulation of drug-resistant mutants. Furthermore, the decrease of cellular HIV-1 DNA to low absolute levels in those without genetic evidence of viral replication suggests that monitoring viral DNA during HAART may gauge low-level replication.

Antiretroviral Therapy, Highly Active↗

PubMed2006

Antiviral drug resistance.

Almost 30 years ago it was proposed that the selection for antiviral drug resistance should be used as an indicator of antiviral drug activity. In addition to discriminating between cellular toxicity and specific activity directed against a viral target, drug resistant mutants have been used to confirm the mechanism of action of antiviral drugs, to discover the functions of several viral proteins and to provide insights into viral evolution and fitness. Drug resistance has also become a standard component of both the preclinical and clinical drug development process. For HIV and increasingly for other viruses drug resistance testing has become standard-of-care in clinical practice. A few selected examples are provided to illustrate each of these points.

Antiviral Agents↗

PubMed2005

Evolutionary feedback mediated through population density, illustrated with viruses in chemostats.

A cornerstone of evolutionary ecology is that population density affects adaptation: r and K selection is the obvious example. The reverse is also appreciated: adaptation impacts population density. Yet, empirically demonstrating a direct connection between population density and adaptation is challenging. Here, we address both evolution and ecology of population density in models of viral (bacteriophage) chemostats. Chemostats supply nutrients for host cell growth, and the hosts are prey for viral reproduction. Two different chemostat designs have profoundly different consequences for viral evolution. If host and virus are confined to the same chamber, as in a predator-prey system, viral regulation of hosts feeds back to maintain low viral density (measured as infections per cell). Viral adaptation impacts host density but has a small effect on equilibrium viral density. More interesting are chemostats that supply the viral population with hosts from a virus-free refuge. Here, a type of evolutionary succession operates: adaptation at low viral density leads to higher density, but high density then favors competitive ability. Experiments support these models with both phenotypic and molecular data. Parallels to these designs exist in many natural systems, so these experimental systems may yield insights to the evolution and regulation of natural populations.

Adaptation, Biological↗

PubMed1991

Rapid antigenic-type replacement and DNA sequence evolution of canine parvovirus.

Analysis of canine parvovirus (CPV) isolates with a panel of monoclonal antibodies showed that after 1986, most viruses isolated from dogs in many parts of the United States differed antigenically from the viruses isolated prior to that date. The new antigenic type (designated CPV type 2b) has largely replaced the previous antigenic type (CPV type 2a) among virus isolates from the United States. This represents the second occurrence of a new antigenic type of this DNA virus since its emergence in 1978, as the original CPV type (CPV type 2) had previously been replaced between 1979 and 1981 by the CPV type 2a strain. DNA sequence comparisons showed that CPV types 2b and 2a differed by as few as two nonsynonymous (amino acid-changing) nucleotide substitutions in the VP-1 and VP-2 capsid protein genes. One mutation, resulting in an Asn-Asp difference at residue 426 in the VP-2 sequence, was shown by comparison with a neutralization-escape mutant selected with a non-CPV type 2b-reactive monoclonal antibody to determine the antigenic change. The mutation selected by that monoclonal antibody, a His-Tyr difference in VP-2 amino acid 222, was immediately adjacent to residue 426 in the three-dimensional structure of the CPV capsid. The CPV type 2b isolates are phylogenetically closely related to the CPV type 2a isolates and are probably derived from a common ancestor. Phylogenetic analysis showed a progressive evolution away from the original CPV type. This pattern of viral evolution appears most similar to that seen in some influenza A viruses.

Amino Acid Sequence↗

PubMed2003

Origins of highly mosaic mycobacteriophage genomes.

Bacteriophages are the most abundant organisms in the biosphere and play major roles in the ecological balance of microbial life. The genomic sequences of ten newly isolated mycobacteriophages suggest that the bacteriophage population as a whole is amazingly diverse and may represent the largest unexplored reservoir of sequence information in the biosphere. Genomic comparison of these mycobacteriophages contributes to our understanding of the mechanisms of viral evolution and provides compelling evidence for the role of illegitimate recombination in horizontal genetic exchange. The promiscuity of these recombination events results in the inclusion of many unexpected genes including those implicated in mycobacterial latency, the cellular and immune responses to mycobacterial infections, and autoimmune diseases such as human lupus. While the role of phages as vehicles of toxin genes is well established, these observations suggest a much broader involvement of phages in bacterial virulence and the host response to bacterial infections.

Autoimmune Diseases↗