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PubMed1995

Molecular evolution of aphthoviruses.

Aphthoviruses are an important group of animal pathogens. A combination of genetic and structural studies has revealed one of the main principles governing their evolution: severe limitations to variation imposed by functional and structural constraints, in conjunction with high mutation and recombination rates operating during genome replication. Evolution occurs by positive selection and random drift acting on complex quasispecies distributions. The mutant composition of a quasi-species (or mutant spectrum) is largely dictated by tolerance to nucleotide and amino acid substitutions in viral RNAs and proteins, which must remain functionally competent. We review recent evidence to support this proposal, and we suggest that similar concepts may apply to other RNA viruses as well.

Adaptation, Physiological↗
PubMed2001

Genetic 'budget' of viruses and the cost to the infected host: a theory on the relationship between the genetic capacity of viruses, immune evasion, persistence and disease.

The nature of the pathogen-host relationship is recognized as being a dynamic coevolutionary process where the immune system has required ongoing adaptation and improvement to combat infection. Under survival pressure from sophisticated immune responses, adaptive processes for microbes, including viruses, have manifested as immune evasion strategies. This paper proposes a theory that virus immune evasion can be broadly classified into 'acquisition' or 'erroneous replication' strategies. Acquisition strategies are characteristic of large genome dsDNA viruses, which (i) replicate in the cell nucleus; (ii) have acquired host genes that can be used to directly manipulate responses to infection; (iii) are often latent for the lifetime of the host; and (iv) have little or no serious impact on health. Alternatively, erroneous replication strategies are characteristic of small genome RNA viruses, which are recognized as being the cause of many serious diseases in humans. It is proposed that this propensity for disease is due to the cytoplasmic site of replication and truncated temporal relationship with the host, which has limited or removed the evolutionary opportunity for RNA viruses to have acquired host genes. This has resulted in RNA viruses relying on error-prone replication strategies which, while allowing survival and persistence, are more likely to lead to disease due to the lack of direct viral control over potentially host-deleterious inflammatory and immune responses to infection.

Animals↗
PubMed2005

RNA recombination of hepatitis delta virus in natural mixed-genotype infection and transfected cultured cells.

Most RNA viruses encode their own RNA polymerases for genome replication, and increasing numbers of them appear to be capable of undergoing RNA recombination. Here, we provide the first report of intergenotypic recombination in hepatitis delta virus (HDV), the only animal RNA virus that requires host RNA polymerase(s) for viral replication. In vivo, we analyzed RNA species derived from the serum of a patient with mixed genotype I and genotype IIb HDV infection by using multiple restriction fragment length polymorphism (RFLP) assays and sequence analysis of cloned reverse transcription (RT)-PCR products. Six HDV recombinants were isolated from 101 tested clones, and HDV recombination in this patient was further confirmed by RT-PCR with genotype-specific primer pairs. Analysis of the recombination junctions suggested that the HDV genome rearrangement occurred through faithful homologous recombination. We then used an RNA cotransfection cell culture system to investigate HDV RNA recombination in vitro. We found that HDV recombinants could indeed be detected in the transfected cells; some of these possessed recombination junctions identical to those identified in vivo. Furthermore, using a PCR-independent RNase protection assay, we were able to readily identify the recombined HDV RNA species in cultured cells. Taken together, our results demonstrate that HDV RNA recombination occurs in both natural HDV infections and cultured cells, thereby presenting a novel mechanism for HDV evolution.

Amino Acid Sequence↗
PubMed2006

Extensive recombination among human immunodeficiency virus type 1 quasispecies makes an important contribution to viral diversity in individual patients.

Although recombination during human immunodeficiency virus type 1 (HIV-1) replication in vitro and in vivo has been documented, little information is available concerning the extent that recombination contributes to the diversity of HIV-1 quasispecies in the course of infection in individual patents. To investigate the impact of recombination on viral diversity, we developed a technique that permits the isolation of contemporaneous clonal viral populations resulting from single infectious events by plasma-derived viruses, thereby permitting the assessment of recombination throughout the viral genomes, including widely separated loci, from individual patients. A comparison of the genomic sequences of clonal viruses from six patients, including patients failing treatment with antiretroviral therapy, demonstrated strong evidence for extensive recombination. Recombination increased viral diversity through two distinct mechanisms. First, evolutionary bottlenecks appeared to be restricted to minimal segments of the genome required to obtain selective advantage, thereby preserving diversity in adjacent regions. Second, recombination between adjacent gene segments appeared to generate diversity in both pol and env genes. Thus, the shuffling of resistance mutations within the genes coding for the protease and reverse transcriptase, as well as recombination between these regions, could increase the diversity of drug resistance genotypes. These findings demonstrate that recombination in HIV-1 contributes to the diversity of viral quasispecies by restricting evolutionary bottlenecks to gene segments and by generating novel genotypes in pol and env, supporting the idea that recombination may be critical to adaptive evolution of HIV in the face of constantly moving selective pressures, whether exerted by the immune system or antiretroviral therapy.

Amino Acid Sequence↗
PubMed2025

Genome-scale evolution and phylodynamics of swine influenza A viruses in China: a genomic epidemiology study.

BACKGROUND: Pigs are recognised as crucial intermediate hosts for the emergence of influenza viruses of pandemic potential. As the largest pork-producing nation, China hosts a complex ecosystem of swine influenza viruses (SIVs). We aimed to investigate the evolutionary processes, spatiotemporal dynamics, and biological characteristics of SIVs in China. METHODS: From Jan 15, 2016, to Dec 22, 2020, we collected nasal swabs from pigs at eight abattoirs and 16 swine farms in the Guangdong, Henan, and Shandong provinces of China, as part of SIV surveillance. SIVs were detected with RT-PCR. Positive samples underwent viral isolation and genome sequencing. We analysed evolution and spatiotemporal dynamics using the whole genomes of isolated SIVs, as well as genome sequences of SIV isolates from human infections worldwide retrieved from the Global Initiative on Sharing All Influenza Data and GenBank Flu databases up to April 28, 2024. Viral sequences without a sample collection area or date were excluded from the analysis. Viral receptor-binding properties and in-vitro replication of strains isolated in this study were evaluated with a solid-phase binding assay and various cell lines, including Madin-Darby canine kidney cells, porcine alveolar macrophages, primary porcine trachea epithelial cells, human bronchial epithelioid, and human lung adenocarcinoma epithelial (A549) cells. Viral replication and transmission studies were conducted in 33 guinea pigs and 13 pigs. Additionally, we collected serum samples from pig farm workers and members of the general public recruited by the Third Affiliated Hospital of Sun Yat-sen University between Feb 28 and May 11, 2023, to detect specific antibodies against Eurasian avian-like A(H1) and human-like A(H3N2) SIVs using the haemagglutination inhibition assay. FINDINGS: 23 (1·3%) of 1818 nasal swabs collected in abattoirs had SIVs; 22 (0·9%) of 2375 swabs from swine farms had SIVs. Further viral isolation yielded 39 strains of SIV. We identified 534 A(H1N1), 69 A(H1N2), and 92 A(H3N2) SIVs, representing 20 genotypes within the Eurasian avian-like lineage, 14 within the classical swine A(H1) lineage, and 16 within the human-like A(H3N2) lineage. The introduction of the A(H1N1)pdm/09 virus significantly influenced the internal gene pool of SIVs, enhancing genotypic diversity in China. Notably, the Eurasian avian-like A(H1), classical swine A(H1), and human-like A(H3N2) lineages showed human-mediated spread over long distances between provinces, with the Eurasian avian-like A(H1) lineage showing the most prevalent spread pathways. Eurasian avian-like A(H1) SIVs showed a preference for binding to sialic acid α-2,6 glycan receptors, predominantly found in humans, resulting in an increased production of progeny viruses in human airway epithelial cells, as well as effective transmission and infectivity among guinea pigs and pigs. Among 54 eligible serum samples collected from pig farm workers (24 from slaughterhouses and 30 from swine farms), 23 (43%) were seropositive for Eurasian avian-like A(H1) SIVs and 46 (85%) for human-like A(H3N2) SIVs. Among 100 eligible samples from members of the general public, 14 (14%) were seropositive for Eurasian avian-like A(H1) SIVs and 85 (85%) for human-like A(H3N2) SIVs. INTERPRETATION: This study elucidates the evolutionary processes and spatiotemporal patterns of SIVs, highlighting potential risks to public health. These findings are crucial for informing public health interventions that aim to prevent future SIV epidemics in China and other countries worldwide. FUNDING: Scientific Innovation Strategy-Construction of High-Level Academy of Agriculture Science-Distinguished Scholar (R2020PY-JC001).

Animals↗
PubMed2003

Inference of viral evolutionary rates from molecular sequences.

The processes of mutation and nucleotide substitution contribute to the observed variability in virulence, transmission and persistence of viral pathogens. Since most viruses evolve many times faster than their human hosts, we are in the unusual position of being able to measure these processes directly by comparing viral genes that have been isolated and sequenced at different points in time. The analysis of such data requires the use of specific statistical methods that take into account the shared ancestry of the sequences and the randomness inherent in the process of nucleotide substitution. In this paper we describe the various statistical methods for estimating evolutionary rates, which can be classified into three general approaches: linear regression, maximum likelihood, and Bayesian inference. We discuss the advantages and shortcomings of each approach and illustrate their use through the analysis of two example viruses; human immunodeficiency virus type 1 and dengue virus serotype 4. Reliable estimates of viral substitution rates have many important applications in population genetics and phylogenetics, including dating evolutionary events and divergence times, estimating demographic parameters such as population size and generation time, and investigating the effect of natural selection on molecular evolution.

Base Sequence↗
PubMed2005

New evolutionary frontiers from unusual virus genomes.

The sequences of two giant viral genomes, Mimivirus and a polydnavirus, have recently been published. Mimivirus has the largest known viral genome and encodes an unprecedented number of proteins, whereas the polydnavirus genome has an extremely low coding density and does not encode DNA-replication proteins. These and other unusual features challenge the way we view the evolution and definition of viruses.

Animals↗
PubMed2006

A circadian model for viral persistence.

Persistently infecting DNA viruses depend heavily on host cell DNA synthesis machinery. Replication of cellular and viral DNA is inhibited by mutagenic stress. It is hypothesized that diurnal regulation of viral DNA replication may occur at the level of cell cycle checkpoints and DNA repair, to protect DNA from exposure to UV light or other mutagens. This highly conserved mechanism is traced back to viruses that persist in prokaryotes and eukaryotes. Inhibition of viral DNA replication and the cell cycle in response to UV light may represent a functional building block in the evolution of circadian-gated DNA replication. Viral DNA replication appears to be closely linked to the circadian clock by interaction of viral promoters, early viral proteins and transcription factors. It is proposed here that under certain conditions viral oncogene expression is phase-shifted relative to that of tumor suppressor and DNA repair genes. The resulting desynchrony of checkpoint controls and DNA repair from diurnal genotoxic exposure produces cyclic periods of suboptimal response to DNA damage. This temporal vulnerability to genotoxic stress produces a "mutator phenotype" with inherent genome instability. The proposed model delineates areas of research with implications for viral pathogenesis and therapeutics.

Cell Cycle↗
PubMed2004

[Pathogenesis, clinical picture, and diagnosis of myopericarditides].

Basing on own data and literature survey the authors analyze clinical course of viral myopericarditides. Special emphasis is made on evolution of electrocardiographical signs in which four stages are distinguished. It is noted that incidence of hemorrhagic myopericarditides probably of viral nature is increasing. The paper contains recommendations on treatment of patients with myopericarditis. The disease has favorable prognosis. However prognosis of diffuse myopericarditis remains unfavorable and its rational treatment - insufficiently established.

Electrocardiography↗
PubMed2000

Evolution of the T cell repertoire during primary, memory, and recall responses to viral infection.

Many viral infections induce a broad repertoire of CD8(+) T cell responses that initiate recognition and elimination of infected cells by interaction of TCRs with viral peptides presented on infected cells by MHC class I proteins. Following clearance of the infection, >90% of activated CD8(+) T cells die, leaving behind a stable pool of memory CD8(+) T cells capable of responding to subsequent infections with enhanced kinetics. To probe the mechanisms involved in the generation of T cell memory, we compared primary, memory, and secondary challenge virus-specific T cell repertoires using a combination of costaining with MHC class I tetramers and a panel of anti-Vss Abs, as well as complementarity-determining region 3 length distribution analysis of TCR Vss transcripts from cells sorted according to tetramer binding. Following individual mice over time, we found identity between primary effector and memory TCR repertoires for each of three immunodominant epitopes from lymphocytic choriomeningitis virus. During secondary responses, we found quantitative changes in epitope-specific T cell hierarchies but little evidence for changes in Vss usage or complementarity-determining region 3 length distributions within epitope-specific populations. We conclude that 1) selection of memory T cell populations is stochastic and not determined by a distinct step of clonal selection necessary for survival from the acute responding population, and 2) maturation of the T cell repertoire during secondary lymphocytic choriomeningitis virus infection alters the relative magnitudes of epitope-specific responses but does not significantly modify the repertoire of T cells responding to a given epitope.

Animals↗
PubMedDate not supplied

[Antigenic determinant study of the hemagglutinin in the composition of influenza viruses A subtype H1N1 by an indirect solid-phase radioimmunological analytical method].

A comparative study of antigenic determinants of influenza A virus, subtype H1N1, hemagglutinins isolated in 1947-1953 and in 1977-1979 was carried out. The competitive capacity of 8 virus strains for antibody of 4 hyperimmune antisera to A/Fm/1/47, A/Moscow/Pan/52, A/USSR/090/77, and A/Brazil/11/78 viruses was studied by solid-phase radioimmunoassay (SPRIA) in two modifications: in the homologous and heterologous systems. The analysis of competition in the heterologous system permits one to study isolated subpopulations of antibody homologous to viruses fixed on the solid phase. The combination of both modifications allows investigations of a wider spectrum of antibodies than those possible in the homologous system alone. The results of the study showed the antigenic determinants of hemagglutinin exposed on the surface of particles of different influenza A virus strains to differ in their capacity to stimulate antibody synthesis. The analysis of the time course of changes in the antigenic properties of hemagglutinin regions of similar structure in various viral strains may facilitate prognosing of evolution of virus strains of the same subtype.

Animals↗
PubMed2006

Low genetic barrier to large increases in HIV-1 cross-resistance to protease inhibitors during salvage therapy.

HIV-1 resistance to protease inhibitors (PIs) is characterized by extensive cross-resistance within this drug class. Some PIs, however, appear less affected by cross-resistance and are often prescribed in salvage therapy regimens for patients who have failed previous PI treatment. To examine the capacity of HIV-1 to adapt to these treatment changes, we have followed the evolution of HIV-1 protease genotypes and phenotypes in 21 protease-inhibitor-experienced patients in whom 26 weeks of an aggressive salvage regimen associating lopinavir, amprenavir and ritonavir failed to suppress viral replication. Baseline genotypes exhibited a median of seven resistance mutations in the protease. After 26 weeks of treatment, changes in protease genotypes were seen in 13/21 patients. The evolution of these protease genotypes was rapid, with more than one-third of the changes occurring during the first 6 weeks. Although the mean number of additional mutations was small (2.15 new mutations at week 26) these mutations were sufficient to promote remarkable changes in resistance phenotype. In several patients, some of the new mutations were found to exist before salvage treatment as part of minority quasi-species. Thus, in the face of the strong pharmacological pressure exerted by combinations of PIs to which it has never been exposed, and in spite of limited cross-resistance to these drugs before salvage therapy, HIV-1 can rapidly adapt its resistance genotype and phenotype at a minimal evolutionary cost.

Drug Administration Schedule↗
PubMed2006

The symptomless leaf infection with grapevine leafroll associated virus 3 in grown in vitro plants as a simple model system for investigation of viral effects on photosynthesis.

The photosynthetic changes evaluated by oxygen evolution, chlorophyll fluorescence, photoacoustics, and delayed fluorescence (DF) were studied in leaves of grown in vitro for 8 weeks grapevine plants (Vitis vinifera) infected by grapevine leafroll-associated virus 3 (GLRaV-3). The infected leaves were characterized during the viral infection without visible disease symptoms. The symptomless infection led to a decrease in plant biomass. The non-photochemical fluorescence quenching, qN, declined, whereas the photochemical quenching, qP, and the Chl a/b ratio were not significantly affected. Photoacoustic and oxygen evolution measurements showed that the energy storage and oxygen evolution rate decreased in the infected leaves. Enhanced alternative electron sinks during the symptomless viral infection were also estimated. The changes in fluorescence and DF temperature curves demonstrated an enhanced stability of the thylakoid membranes in the infected leaves. This effect was clearly expressed at high actinic light intensities. The viral infected in vitro grown grapevine plants were used in the present study as a simplified model system that allow to avoid the involvement of different environmental factors that could interfere with the GLRaV infection and the virus-grapevine interactions. Thus, the 'pure' impact of the viral infection on photosynthesis could be investigated.

Chlorophyll↗
PubMed2005

Molecular evolution of the plant virus family Bromoviridae based on RNA3-encoded proteins.

We have carried out an evolutionary study of the two proteins encoded by the RNA 3 from members of the plant virus family Bromoviridae. Using maximum likelihood methods, we have inferred the patterns of amino acid substitution that better explain the diversification of this viral family. The results indicate that the molecular evolution of this family was rather complex, with each protein evolving at different rates and according to different patterns of amino acid substitution. These differences include different amino acid equilibrium frequencies, heterogeneity in substitution rates among sites, and covariation among sites. Despite these differences, the model of protein evolution that better fits both proteins is one specifically proposed for the evolution of globular proteins. We also found evidence for coevolution between domains of these two proteins. Finally, our analyses suggest that the molecular clock hypothesis does not hold, since different lineages evolved at different rates. The implications of these results for the taxonomy of this important family of plant viruses are discussed.

Bromoviridae↗
PubMedDate not supplied

[West Nile virus genotyping among wild birds belonging to ground and tree-brush bird populations on the territories of the Baraba forest-steppe and Kulunda steppe (2003-2004)].

The paper gives the results of the 2003-2004 examinations of 104 wild birds belonging to land tree-brush complexes from the Baraba forest-steppe and Kulunda steppe for the detection and genotyping West Nile virus (WNV). ELISA and RT-PCR were used to show that in the forest-steppe and steppe zones of the south of Western Siberia, WNV circulates among both migrating and settled birds. An analysis of the nucleotide sequence of a protein E gene fragment showed the circulation of WNV genotype Ia in the study birds. A number of revealed amino acid substitutions in surface glycoprotein E are unique for the 2003-2004 Western-Siberian WNV variants and absent in the 2002 Western-Siberian variants, which suggests that there are regional features of the evolution of WNV genotype Ia.

Amino Acid Sequence↗
PubMed1986

Immune thrombocytopenic purpura associated with hepatitis A.

A 23-year-old man developed thrombocytopenic purpura at the end of the second week of the clinical evolution of hepatitis A confirmed by viral markers. The bone marrow of this patient showed megakaryocytic hyperplasia. Circulating in his serum immune complexes were demonstrated by solid phase conglutinin enzymo-immunoassay. Platelet-reactive serum factors were also detected by an indirect immunofluorescence test using fresh donor platelets as targets. The evolution of both the hepatitis and the purpura were benign with no therapy other than bedrest. Platelet count normalized within five weeks of the onset of purpura, and IgM antibodies against hepatitis A virus as well as circulating immune complexes dropped to normal levels. It is postulated that the thrombocytopenia of this case was caused by nonspecific deposition of immune complexes at the platelet surface.

Adult↗
PubMed2025

Intracellular interactions shape antiviral resistance outcomes in poliovirus via eco-evolutionary feedback.

Antiviral resistance evolution poses a major obstacle for controlling viral infections. A promising strategy is to target shared viral proteins that allow drug susceptible viruses to sensitize resistant ones during cellular coinfection, muting selection for resistance. Pocapavir, a poliovirus capsid inhibitor, employs this sociovirological strategy. While susceptible viruses significantly suppressed resistance in the presence of pocapavir in cell culture, a pocapavir clinical trial observed widespread resistance evolution and limited improvements to clearance times. To reconcile these findings, we present an intra-host eco-evolutionary model of poliovirus in the presence of pocapavir, which reproduces both the potent interference observed in vitro and the resistance emergence seen in patients. In the short term, our model predicts that a high density of susceptible viruses sensitizes resistant ones to pocapavir, mirroring cell culture results. However, over multiple replication cycles, pocapavir's high potency collapses viral density, which reduces coinfection and allows resistance to evolve as observed in the clinical trial. Since coinfection is essential to suppress resistance, enabling greater survival of susceptible viruses could offer therapeutic advantages. Counterintuitively, we demonstrate that this can be achieved by lessening antiviral potency, which can limit resistance evolution while also maintaining a low viral load. These findings suggest that antivirals that rely on viral intracellular interaction must balance immediate neutralization with the preservation of future coinfection, yielding more sustained inhibition. Explicitly considering the eco-evolutionary feedback encompassing viral density, shared phenotypes and absolute fitness not only provides new insights into designing effective therapies but also illuminates viral evolutionary dynamics more broadly.

Journal Article↗
PubMed2004

Cellular source of the poxviral N1R/p28 gene family.

Full-length poxvirus N1R/p28 orthologous proteins feature a prominent C-terminal RING zinc-finger motif. The RING moiety is conspicuously mutated in a number of vaccinia virus strains relative to variola virus. This, together with empirical data, suggests that N1R/p28 proteins promote virulence by suppressing apoptosis. Poxvirus N1R/p28 orthologues are strikingly similar to the RING motif of the cellular Makorin family of zinc-finger proteins, suggesting a homologous relationship connecting the viral and cellular genes. Recently identified avipox N1R/p28 orthologues further encode additional Makorin-like zinc-finger motifs, consistent with this suggestion. Phylogenetic analysis supports a model of poxviral capture of a MKRN cDNA and fusion with an existing viral gene. Establishing an evolutionary link between the viral and cellular genes will facilitate the elucidation of their respective cellular functions, and of how they interact in modulating virulence.

Animals↗