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PubMed1996

Questions on the evolution of primate T-lymphotropic viruses raised by molecular and epidemiological studies of divergent strains.

In human and simian T-lymphotropic viruses (HTLV and STLV), collectively referred to as primate T-lymphotropic viruses (PTLV), four distinct clades can be distinguished: PTLV-I, PTLV-II, and the newly discovered divergent STLVs isolated from hamadryas baboons and from bonobos (pygmy chimpanzees). The hamadryas STLV is clearly distinct from types I and II, in terms both of sequence divergence and of genomic structure, and would qualify as a separate type, provisionally called PTLV-L. The bonobo STLV is closer to, although clearly distinct from, PTLV-II, at present known only in humans. While PTLV-II, PTLV-L, and the bonobo STLV appear presently to be species specific, PTLV-I has spread during its evolution through repeated interspecies transmissions between primates and is now present in many species of Old World monkeys and apes and in humans. The human subtypes of PTLV-I arose from at least three acquisitions from separate simian reservoirs.

Animals↗
PubMed2005

Ancient co-speciation of simian foamy viruses and primates.

Although parasite-host co-speciation is a long-held hypothesis, convincing evidence for long-term co-speciation remains elusive, largely because of small numbers of hosts and parasites studied and uncertainty over rates of evolutionary change. Co-speciation is especially rare in RNA viruses, in which cross-species transfer is the dominant mode of evolution. Simian foamy viruses (SFVs) are ubiquitous, non-pathogenic retroviruses that infect all primates. Here we test the co-speciation hypothesis in SFVs and their primate hosts by comparing the phylogenies of SFV polymerase and mitochondrial cytochrome oxidase subunit II from African and Asian monkeys and apes. The phylogenetic trees were remarkably congruent in both branching order and divergence times, strongly supporting co-speciation. Molecular clock calibrations revealed an extremely low rate of SFV evolution, 1.7 x 10(-8) substitutions per site per year, making it the slowest-evolving RNA virus documented so far. These results indicate that SFVs might have co-speciated with Old World primates for at least 30 million years, making them the oldest known vertebrate RNA viruses.

Animals↗
PubMed1993

Evolution and replication of tobacco ringspot virus satellite RNA mutants.

The replication properties of linker insertion-deletion mutants of tobacco ringspot virus satellite RNA have been studied by amplification in plants infected with the helper virus. Sequence analysis of the cDNAs corresponding to the replicated forms shows that only one of the original mutated molecules replicates unaltered, and in general new variants accumulate. Depending on the location of the original mutation three types of sequence modifications were observed: (i) deletion of the mutated region followed by sequence duplication, (ii) sequence duplication and deletion outside of the mutated region and (iii) limited rearrangements at the site of mutation. The mutant that replicates without sequence changes accumulates linear multimeric forms suggesting that self-cleavage is affected although the sequence alteration does not involve the hammerhead catalytic domain. Alternative RNA conformations are likely to play a role in the origin of this phenotype and in the formation of sequence duplications. These results demonstrate the great structural flexibility of this satellite RNA.

Base Sequence↗
PubMed1989

Rapid, random evolution of the genetic structure of replicating tobacco mosaic virus populations.

The effects of temperature and type of host on the evolution of variants in replicating populations of tobacco mosaic virus (TMV) originating from an in vitro RNA transcript of a cDNA clone were studied. The phenotypic markers measured were temperature-sensitive (ts) replication and induction of necrotic local lesions (nl) on Nicotiana sylvestris. The proportions of ts variants were about the same under all conditions tested, but changes in temperature or host had strong effects on proportions of nl variants. During replication at elevated temperatures in tobacco or tomato, percentages of nl variants were reduced rapidly to about one tenth their initial values. In contrast, when virus replicated at 25 degrees in tobacco, little change in the average proportion of nl variants was observed, and in tomato, only a slight average reduction occurred. Virus replicating at 25 degrees in Solanum nigrum or Petunia hybrida suffered effects similar to those observed in tobacco or tomato, respectively. However, at 25 degrees in Physalis floridana, there was strong selection against nl variants, which eventually reduced them to essentially undetectable levels. In all hosts tested at 25 degrees, surprisingly large, apparently random changes in the proportion of nl variants occurred in individual plants. These experiments showed that virus populations can evolve rapidly on a time scale of days, and that an element of randomness is an important component in the initiation of change.

Biological Evolution↗
PubMed1999

Evolution by small steps and rugged landscapes in the RNA virus phi6.

Fisher's geometric model of adaptive evolution argues that adaptive evolution should generally result from the substitution of many mutations of small effect because advantageous mutations of small effect should be more common than those of large effect. However, evidence for both evolution by small steps and for Fisher's model has been mixed. Here we report supporting results from a new experimental test of the model. We subjected the bacteriophage phi6 to intensified genetic drift in small populations and caused viral fitness to decline through the accumulation of a deleterious mutation. We then propagated the mutated virus at a range of larger population sizes and allowed fitness to recover by natural selection. Although fitness declined in one large step, it was usually recovered in smaller steps. More importantly, step size during recovery was smaller with decreasing size of the recovery population. These results confirm Fisher's main prediction that advantageous mutations of small effect should be more common. We also show that the advantageous mutations of small effect are compensatory mutations whose advantage is conditional (epistatic) on the presence of the deleterious mutation, in which case the adaptive landscape of phi6 is likely to be very rugged.

Bacteriophage phi 6↗
PubMed2005

Mode of selection and experimental evolution of antiviral drugs resistance in vesicular stomatitis virus.

The possession of an antiviral resistance mutation benefits a virus when the corresponding antiviral is present. But does the resistant virus pay a fitness cost when the antiviral is absent? Would an evolutionary history of association between a genotype and a resistance mutation overcome this cost by changes compensating the harmful side-effect of resistance mutations? Are combined therapies more effective against the rise of resistant viruses or against evolutionary compensations? To explore all these questions, we took an experimental evolution approach. After selecting vesicular stomatitis virus (VSV) populations able to replicate under increasing concentrations of ribavirin and/or alpha-interferon, we evolved them for more than 100 generations under sub-inhibitory concentrations of the corresponding antivirals, allowing for evolutionary compensation. Our results show that resistance for these two antivirals was not easily achieved, being the selected populations generally less fit than the ancestrals both in presence and absence of the antivirals. Evolution in presence of sub-inhibitory concentrations of antivirals compensated for the reduction in fitness in presence of antiviral therapy.

Antiviral Agents↗
PubMed2005

Isolation of virus from a SARS patient and genome-wide analysis of genetic mutations related to pathogenesis and epidemiology from 47 SARS-CoV isolates.

Severe acute respiratory syndrome (SARS) caused by SARS-associated coronavirus (SARS-CoV) is a fatal disease. Prevention of future outbreaks is essential and requires understanding pathogenesis and evolution of the virus. We have isolated a SARS-CoV in China and analyzed 47 SARS-CoV genomes with the aims to reveal the evolution trends of the virus and provide insights into understanding pathogenesis and SARS epidemic. Specimen from a SARS patient was inoculated into cell culture. The presence of SARS-CoV was determined by RT-PCR and confirmed by electron microscopy. Virus was isolated followed by the determination of its genome sequences, which were then analyzed by comparing with other 46 SARS-CoV genomes. Genetic mutations with potential implications to pathogenesis and the epidemic were characterized. This viral genome consists of 29,728 nucleotides with overall organization in agreement with that of published isolates. A total of 348 positions were mutated on 47 viral genomes. Among them 22 had mutations in more than three genomes. Hot spots of nucleotide variations and unique trends of mutations were identified on the viral genomes. Mutation rates were different from gene to gene and were correlated well with periodical or geographic characteristics of the epidemic.

Adolescent↗
PubMed1993

Evolution of mouse mammary tumor virus-related sequences in the human genome.

The human genome contains numerous copies of elements with sequence homology to the mouse mammary tumor virus (MMTV). We have been interested in whether these elements are still actively transposing in the germ lines, and investigated this question by looking at restriction fragment patterns. Genomic DNA from humans and selected animals were digested with three different restriction enzymes and hybridized with five probes representative of five subgroups of the human MMTV-related elements. Two polymorphisms as well as two cases of sexual dimorphism were discovered in human DNA. The latter indicate the presence of at least two elements of the MMTV family on the Y chromosome. DNA samples from non-primate mammals were all unreactive. Both chimpanzee and rhesus monkey had restriction patterns of roughly the same number of bands and total intensity as humans. The number of differences in patterns between humans, and between humans and chimpanzee or rhesus monkey, were compatible with being caused by point mutations. The data indicate that these elements were actively spreading in the genome some time before the split between apes and Old World monkeys, while being relatively inactive, at least as to transpositions in the germ line, in later ages.

Animals↗
PubMed1988

Genetic stability of Ross River virus during epidemic spread in nonimmune humans.

We have examined the rate of evolution of Ross River virus, a mosquito-borne RNA virus, during epidemic spread through tens of thousands of nonimmune humans over a period of 10 months. Two regions of the Ross River virus genome were sequenced: the E2 gene (1.2 kb in length), which encodes the major neutralization determinant of the virus, and 0.4 kb of the 3'-untranslated region. In the E2 gene, a single nucleotide change was selected which led to a predicted amino acid change at residue 219. No changes were selected in the 3'-untranslated region. By comparison with rates of evolution reported for non-arthropod-borne RNA viruses, the rate for Ross River virus is surprisingly low. We identify three features of the Ross River virus replication and transmission cycle which may limit the rate of evolution of arthropod-borne viruses in the field.

Alphavirus↗
PubMed2004

Attenuation of Sindbis virus variants incorporating uncleaved PE2 glycoprotein is correlated with attachment to cell-surface heparan sulfate.

Sindbis virus virions incorporating uncleaved precursor envelope protein PE2 bind efficiently to cell-surface heparan sulfate (HS) because the furin cleavage site (a consensus HS-binding domain) is retained in the mature virus particle. However, they are essentially nonviable. Resuscitating mutations selected in the E3 or E2 protein preserve the PE2 noncleaving phenotype and HS binding, but facilitate fusion, and thereby restore wild-type infectivity on cultured cells. Here, we have demonstrated that the resuscitated PE2 noncleaving virus was almost avirulent in vivo, but mutated during the infection. Mutants had increased virulence and cleavage of PE2, with reduced HS binding capacity. We hypothesize that HS binding leads to sequestration of PE2 noncleaving virus particles and suppression of serum viremia, thereby selecting for evolution of the virus into a PE2-cleaving, low HS-binding phenotype.

Alphavirus Infections↗
PubMed2005

The factors of virulence of influenza a virus.

This review deals with factors that influence the virulence of influenza A virus. A high genetic and antigenic variability is demonstrated in a broad spectrum of influenza A viruses ranging from avirulent to lethal ones. Influenza A viruses have caused several epidemics and pandemics in the past and present that have cost millions of lives worldwide. Therefore these viruses still belong to the most important ones with strong impact on whole human population. Here, we discuss the latest findings concerning the role of individual viral proteins, interaction of the virus with the host immune system, and interspecies transmission and evolution of the virus. It is important to elucidate the genetic background of virulence of influenza A viruses, mechanisms involved in crossing the interspecies barrier, and mechanisms of destruction of the host cell by these viruses, and to identify the factors influencing the interaction between these viruses and the host immune defense system. This knowledge should help to estimate the threat of influenza A viruses with human pandemic potential to human population.

Adaptation, Physiological↗
PubMed2005

Evolution of the equine infectious anemia virus long terminal repeat during the alteration of cell tropism.

Equine infectious anemia virus (EIAV) is a lentivirus with in vivo cell tropism primarily for tissue macrophages; however, in vitro the virus can be adapted to fibroblasts and other cell types. Tropism adaptation is associated with both envelope and long terminal repeat (LTR) changes, and findings strongly suggest that these regions of the genome influence cell tropism and virulence. Furthermore, high levels of genetic variation have been well documented in both of these genomic regions. However, specific EIAV nucleotide or amino acid changes that are responsible for cell tropism changes have not been identified. A study was undertaken with the highly virulent, macrophage-tropic strain of virus EIAV(wyo) to identify LTR changes associated with alterations in cell tropism. We found the stepwise generation of a new transcription factor binding motif within the enhancer that was associated with adaptation of EIAV to endothelial cells and fibroblasts. An LTR that contained the new motif had enhanced transcriptional activity in fibroblasts, whereas the new site did not alter LTR activity in a macrophage cell line. This finding supports a previous prediction that selection for new LTR genetic variants may be a consequence of cell-specific selective pressures. Additional investigations of the EIAV(wyo) LTR were performed in vivo to determine if LTR evolution could be detected over the course of a 3-year infection. Consistent with previous in vivo findings, we observed no changes in the enhancer region of the LTR over that time period, indicating that the EIAV(wyo) LTR was evolutionarily stable in vivo.

Adaptation, Physiological↗
PubMed2005

Selective escape from CD8+ T-cell responses represents a major driving force of human immunodeficiency virus type 1 (HIV-1) sequence diversity and reveals constraints on HIV-1 evolution.

The sequence diversity of human immunodeficiency virus type 1 (HIV-1) represents a major obstacle to the development of an effective vaccine, yet the forces impacting the evolution of this pathogen remain unclear. To address this issue we assessed the relationship between genome-wide viral evolution and adaptive CD8+ T-cell responses in four clade B virus-infected patients studied longitudinally for as long as 5 years after acute infection. Of the 98 amino acid mutations identified in nonenvelope antigens, 53% were associated with detectable CD8+ T-cell responses, indicative of positive selective immune pressures. An additional 18% of amino acid mutations represented substitutions toward common clade B consensus sequence residues, nine of which were strongly associated with HLA class I alleles not expressed by the subjects and thus indicative of reversions of transmitted CD8 escape mutations. Thus, nearly two-thirds of all mutations were attributable to CD8+ T-cell selective pressures. A closer examination of CD8 escape mutations in additional persons with chronic disease indicated that not only did immune pressures frequently result in selection of identical amino acid substitutions in mutating epitopes, but mutating residues also correlated with highly polymorphic sites in both clade B and C viruses. These data indicate a dominant role for cellular immune selective pressures in driving both individual and global HIV-1 evolution. The stereotypic nature of acquired mutations provides support for biochemical constraints limiting HIV-1 evolution and for the impact of CD8 escape mutations on viral fitness.

Acute Disease↗
PubMed1993

Molecular analysis of neurovirulent strains of Sindbis virus that evolve during persistent infection of scid mice.

To understand the role of tissue-specific adaptation and antibody-induced selectional pressures in the evolution of neurovirulent viruses, we analyzed three strains of Sindbis virus isolated from the brains of persistently infected scid mice and four strains of Sindbis virus isolated from the brains of scid mice with viral reactivation following immune serum treatment. For each viral isolate, we tested neurovirulence in weanling BALB/c mice and sequenced regions of the E2 and E1 envelope glycoprotein genes that are known to contain important determinants of Sindbis virus neurovirulence. One strain isolated from a persistently infected scid mouse and two strains isolated from scid mice with viral reactivation were neurovirulent, resulting in mortality in 80 to 100% of weanling BALB/c mice. All three neurovirulent strains contained an A-->U change at nucleotide 8795, which predicts a Gln-->His substitution at E2 amino acid position 55. No nucleotide changes were detected in the other sequenced regions of the E2 and E1 envelope glycoprotein genes or in the avirulent isolates. Our findings indicate that tissue-specific adaptations, rather than antibody-induced selectional pressures, are a critical determinant of the evolution of neurovirulent strains of Sindbis virus and provide evidence that E2 His-55 is an important neuroadaptive mutation that confers neurovirulence properties on Sindbis virus.

Alphavirus Infections↗
PubMed2004

Replication at periodically changing multiplicity of infection promotes stable coexistence of competing viral populations.

RNA viruses are widely used to study evolution experimentally. Many standard protocols of virus propagation and competition are done at nominally low multiplicity of infection (m.o.i.), but lead during one passage to two or more rounds of infection, of which the later ones are at high m.o.i. Here, we develop a model of the competition between wild type (wt) and a mutant under a regime of alternating m.o.i. We assume that the mutant is deleterious when it infects cells on its own, but derives a selective advantage when rare and coinfecting with wt, because it can profit from superior protein products created by the wt. We find that, under these assumptions, replication at alternating low and high m.o.i. may lead to the stable coexistence of wt and mutant for a wide range of parameter settings. The predictions of our model are consistent with earlier observations of frequency-dependent selection in vesicular stomatitis virus and human immunodeficiency virus type 1. Our results suggest that frequency-dependent selection may be common in typical evolution experiments with viruses.

Cell Line↗
PubMed1996

HA1 domain of influenza A (H3N2) viruses in Finland in 1989-1995: evolution, egg-adaptation and relationship to vaccine strains.

The HA1 gene sequences of 22 MDCK cell-derived influenza A (H3N2) strains, ten of their egg-derived counterparts and three vaccine strains were determined. Antigenic and sequence differences between the epidemic and vaccine strains were recorded, most striking in 1992/93; a minority of the amino acid differences in 1989-95 was involved in egg-adaptation. Changes in the assortment of amino acid substitutions produced during egg-adaptation of field strains may account for the difficulty encountered in isolating these viruses in embryonated eggs. Six revertant amino acids, characteristic of field strains prevalent in 1969-71 were recorded in 1994/95. Their genome sequence was interpreted to have been maintained over the interval years among low abundant sequences of the viral quasispecies. Potential changes of carbohydrate moieties were recorded in two glycosylation sites, suggesting that oligosaccharides at these sites are not necessarily advantageous for the H3N2 subtype virus currently.

Adaptation, Physiological↗