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Mechanistic features of recombination in HIV.
The importance of recombination in retroviral evolution has been acknowledged for several decades. Consequently, after the identification of HIV as the etiological agent of AIDS, it was suspected that recombination could also play a central role in the evolution of this virus. However, only recently, extensive epidemiologic studies of HIV infections worldwide have provided an estimate for the occurrence of recombination in vivo, unveiling recombination frequencies that dwarf those initially expected. Nowadays, recombination is regarded as an integral part of the infectious cycle of this retrovirus, which impacts on diagnosis and treatment of infections, especially when genetically distant viruses have been at the origin of the recombinant forms. Retroviral recombination is observed when two genetically divergent genomic RNA molecules are present in the same viral particle, and arises during the reverse transcription step. This review focuses on the mechanisms that have been proposed to account for the occurrence of recombination in retroviruses, from the strand displacement model, according to which recombination occurs during second DNA strand synthesis; to the description of the factors responsible for copy-choice recombination during first DNA strand synthesis, such as the presence of breaks, pause sites, or secondary structures in the genomic RNA. Most of these models have been supported by experimental data obtained from in vitro reconstituted systems or from cell infection studies using academic model sequences. The situation in vivo is expected to be more complex, since several factors come into play when recombination involves relatively distant isolates, as in the case of inter-subtype recombination. At present, it is clear that further studies are needed in order to evaluate whether a prevailing mechanism exists for in vivo recombination, and these studies will also be essential for understanding how the underlying mechanisms of recombination contribute to the evolution of HIV.
Evolution of the L2 gene of strains of bluetongue virus serotype 10 isolated in California.
The genetic characteristics and phylogenetic relationships between the U.S. prototype strain of bluetongue virus serotype 10 (BTV 10), the modified live virus vaccine currently used in California, and three field isolates of BTV 10 obtained in 1980 and three in 1990 in California were determined by comparison of their L2 gene sequences. The L2 genes of the 1980 field isolates were very closely related to the L2 genes of the prototype strain and the vaccine strain, differing by only 0.1 to 0.5%. The 1990 field isolates diverged from all the other viruses by an average of 4.8%. They showed a high degree of genetic similarity that ranged from 98.2 to 99.7% and formed a separate group. All BTV 10 viruses derived from a common ancestor (bootstrap value 100%) from which two different lineages have diverged giving rise to two monophyletic groups, one including all the 1990 viruses and the other the prototype, the vaccine, and all 1980 field strains. The bootstrap analyses placed a 100% confidence value at each of these two nodes. These results indicate that two different lineages of BTV 10 circulated in California between 1953 and 1990. The effect of the vaccine on the evolutionary pathways of the BTV 10 population present in California in 1980 was not clearly established, but it did not influence the evolution of the BTV 10 field isolates obtained in 1990.
Tobacco mosaic virus particle structure and the initiation of disassembly.
The structure of an intact tobacco mosaic virus (TMV) particle was determined at 2.9 A resolution using fibre diffraction methods. All residues of the coat protein and the three nucleotides of RNA that are bound to each protein subunit were visible in the electron density map. Examination of the structures of TMV, cucumber green mottle mosaic virus and ribgrass mosaic virus, and site-directed mutagenesis experiments in which carboxylate groups were changed to the corresponding amides, showed that initial stages of disassembly are driven by complex electrostatic interactions involving at least seven carboxylate side-chains and a phosphate group. The locations of these interactions can drift during evolution, allowing the viruses to evade plant defensive responses that depend on recognition of the viral coat protein surface.
Evolution of the hemagglutinin gene of influenza B virus was driven by both positive and negative selection pressures.
Nucleotide sequences of the hemagglutinin (HA) gene of twelve influenza B strains and their deduced amino acid sequences were extracted from the GenBank and compared to those of early isolates. Separate analyses of nonsynonymous and synonymous substitutions for the HA1 and HA2 regions individually indicate that the percentage of nonsynonymous substitutions in the HA1 ranges from 44.4-56.0% but in the HA2 from 0.0-6.5%. The results suggest that positive selection as well as negative selection played a role in the evolution of the influenza B HA gene with the former acting on the HA1 and the latter on the HA2.
Sequence studies of several alphavirus genomic RNAs in the region containing the start of the subgenomic RNA.
The alphaviruses produce two mRNAs after infection: the genomic (49S) RNA which is translated into the nonstructural (replicase) proteins and the subgenomic (26S) RNA which serves as the mRNA for the virion structural proteins. The sequence of the region of the genomic RNA that contains the 5' end of the subgenomic RNA and the 5' flanking sequences in the genomic RNA were determined for several alphaviruses. A highly conserved sequence of 21 nucleotides was found which includes the first two nucleotides of the subgenomic RNA and the 19 nucleotides preceding it. We propose that the complement of this sequence in the minus strand is the recognition site used by the viral transcriptase for initiation of transcription of 26S RNA and that, in general, such short recognition sequences are commonly used among the RNA viruses. The COOH-terminal sequence of the nonstructural polyprotein precursor has been deduced for each virus. These protein sequences are highly homologous and are followed by multiple in-phase termination codons clustered in the nontranslated region of the 26S RNA in each case. In contrast to the proposed transcriptase recognition site, the particular triplets used for a given conserved amino acid have diverged markedly during evolution of these viruses. The protein homology is sufficient, however, for deduction of the correct coding phase of the RNA and allows the alignment of the corresponding nucleic acid sequence data from different alphaviruses without knowledge of the sequence of the entire genomes.
Drug resistance, virus fitness and HIV-1 mutagenesis.
The evolution of antiretroviral drug resistance is a major problem in the treatment of human immunodeficiency virus type 1 (HIV-1) infection. Drug therapy failure is associated with accumulation of drug resistance mutations and results in the development of drug resistance. Drugs targeted against reverse transcriptase (RT) as well as drug-resistant RT have been shown to increase HIV-1 mutation frequencies. Furthermore, combinations of drug and drug-resistant RT can increase virus mutation frequencies in a multiplicative manner. The evolution of drug resistance also alters virus fitness. The correlation of increased HIV-1 mutation rates with the evolution of antiretroviral drug resistance indicates that drug failure could increase the likelihood of further resistance evolving from subsequent drug regimens. These observations parallel studies from microbial systems that provide evidence for a correlation between drug resistance development and increased pathogen mutation rates. Although increased mutant frequencies may be detrimental to effective therapy, the lethal mutagenesis of the HIV-1 genome may provide a new means for antiretroviral therapy.
Evolution of AZT resistance in HIV-1: the 41-70 intermediate that is not observed in vivo has a replication defect.
The human immunodeficiency virus type 1 (HIV-1) is notorious for its ability to evolve drug-resistance in patients treated with potent antivirals. Resistance to inhibitors of the viral reverse transcriptase (RT) enzyme is frequently mediated by a single amino acid substitution within RT. Resistance against the nucleoside analogue AZT is remarkable in that multiple amino acid changes accumulate over time to yield virus variants with high-level drug resistance. We now report that in addition to drug-resistance properties, the relative replication capacity of the virus variants affects the evolution of AZT resistance. Some of the typical AZT-resistance mutations have a negative impact on virus replication, and the 41-70 double mutant was found to represent a particularly poor virus. Furthermore, introduction of additional AZT-resistance mutations (41-70-215) leads to nearly complete restoration of virus replication. These results may explain the absence of the 41-70 double mutant in clinical samples and indicate that the evolution of AZT resistance is also influenced by virus replication parameters. Prolonged passage of the replication-impaired 41-70 virus in the absence of AZT yielded several fast-replicating variants. These revertants have compensatory changes in the RT polymerase, some of which have been observed previously in AZT-treated patients. Because we could select for these changes without drug pressure, these changes are likely to improve the RT enzyme function and the HIV-1 replication capacity.
Molecular characterization of a wild poliovirus type 3 epidemic in The Netherlands (1992 and 1993).
An outbreak of poliomyelitis due to wild poliovirus type 3 (PV3) occurred in an unvaccinated community in The Netherlands between September 1992 and February 1993. The outbreak involved 71 patients. The aim of this study was to characterize the virus at the molecular level and to analyze the molecular evolution of the epidemic virus. Molecular analysis was carried out by sequencing the VP1/2A junction region (150 nucleotides) of 50 PV3 strains isolated in association with this outbreak and the entire VP1 gene of 14 strains. In addition, the sequence of the VP1/2A junction region of strains from geographical regions endemic for PV3 (Egypt, India, and Central Asia) was analyzed and compared with the nucleotide sequence of the epidemic strain from The Netherlands. The earliest isolate was obtained from river water sampled 3 weeks before diagnosis of the first poliomyelitis patient and was found by VP1/2A sequence analysis to be genetically identical to the strain isolated from the first patient. Sequence divergence among the strains from the epidemic in The Netherlands was less than 2%. The closest genetic similarity (97.3%) was found with an Indian isolate (New Delhi, December 1991), indicating the likely source of the virus. A more than 99% sequence similarity was found in the VP1/2A region. Finally, the sequence information was used to design primers for the specific and highly sensitive molecular detection of PV3 strains during the epidemic.
Extensive sequence variation of feline immunodeficiency virus env genes in isolates from naturally infected cats.
In an investigation of the evolution of feline immunodeficiency virus (FIV) in vivo, sequential isolates from a persistently infected cat were examined by direct sequencing following amplification of selected subgenomic regions by polymerase chain reaction (PCR). Three isolates, T90, T91, and T92, obtained over a three-year period revealed no changes to regions known to be conserved within gag and pol genes. Additionally, no change occurred within gag and pol in an isolate recovered from a second cat which was experimentally infected with T90. Changes were detected within an N-terminal region of the envelope glycoprotein gp 120 (env). These consisted of point mutations, some of which would result in amino acid substitutions and the predicted amino acid changes tended to cluster within variable domains. Inoculation of T90 into a second cat resulted in a different pattern of mutations than that observed for the three isolates from the first cat. In all cases, virus isolates derived from the same cat were much more highly related to each other (extent of env variation was 0.5-1.5%) than to isolates from other cats (10-12% env variation). The rate of change of FIV was estimated to be 3.4 x 10(-3) nucleotide substitutions per site per year for the env gene and less than 10(-4) nucleotide substitutions per site per year for the gag and pol genes, values concordant with that found for human immunodeficiency virus 1. Both nucleotide and amino acid changes in the gp 120 region were found to be directional, suggesting that selective pressures influence FIV envelope gene sequences.
Recombination every day: abundant recombination in a virus during a single multi-cellular host infection.
Viral recombination can dramatically impact evolution and epidemiology. In viruses, the recombination rate depends on the frequency of genetic exchange between different viral genomes within an infected host cell and on the frequency at which such co-infections occur. While the recombination rate has been recently evaluated in experimentally co-infected cell cultures for several viruses, direct quantification at the most biologically significant level, that of a host infection, is still lacking. This study fills this gap using the cauliflower mosaic virus as a model. We distributed four neutral markers along the viral genome, and co-inoculated host plants with marker-containing and wild-type viruses. The frequency of recombinant genomes was evaluated 21 d post-inoculation. On average, over 50% of viral genomes recovered after a single host infection were recombinants, clearly indicating that recombination is very frequent in this virus. Estimates of the recombination rate show that all regions of the genome are equally affected by this process. Assuming that ten viral replication cycles occurred during our experiment-based on data on the timing of coat protein detection-the per base and replication cycle recombination rate was on the order of 2 x 10(-5) to 4 x 10(-5). This first determination of a virus recombination rate during a single multi-cellular host infection indicates that recombination is very frequent in the everyday life of this virus.
Molecular epidemiology of respiratory syncytial virus.
Human respiratory syncytial virus (RSV) is the major cause of lower respiratory tract disease in infants. It is unusual in that it causes repeated infections throughout life. Despite considerable efforts there is as yet no satisfactory vaccine available. This paper reviews the molecular epidemiology of the RSV and describes the complex genotypic structure of RSV epidemics. The evolution of the virus is discussed, with particular reference to the antigenic and genetic variability of the attachment glycoprotein.
Sequence analysis of related low-pathogenic and highly pathogenic H5N2 avian influenza isolates from United States live bird markets and poultry farms from 1983 to 1989.
The last highly pathogenic outbreak of avian influenza in the United States was caused by an H5N2 influenza virus in Pennsylvania and New Jersey in 1983-84. Through a combined federal and state eradication effort, the outbreak was controlled. However, in 1986-89, multiple H5N2 viruses were isolated from poultry farms and the live bird markets (LBMs) in the United States. To determine the epidemiologic relationships of these viruses, the complete coding sequence of the nonstructural gene and the hemagglutinin protein subunit 1 of the hemagglutinin gene was determined for 11 H5N2 viruses and compared with previously available influenza sequences. The H5N2 isolates from 1986-89 were all closely related to the isolates from the 1983-84 Pennsylvania outbreak by nucleotide and amino acid sequence analysis for both genes, providing additional evidence that the Pennsylvania/83 (PA/83) virus lineage was not completely eradicated. The PA/83 lineage also had a large number of unique amino acid changes not found in other avian influenza viruses, which was suggestive that this lineage of virus had been circulating in poultry for an extended period of time before the first isolation of virus in 1983. High substitution and evolutionary rates were measured by examining the number of nucleotide or amino acid substitutions over time as compared with the index case, CK/PA/21525/83. These rates, however, were similar to other outbreaks of avian influenza in poultry. This study provides another example of the long-term maintenance and evolution of influenza viruses in the U.S. LBMs and provides further evidence of the connection of the LBMs and the Pennsylvania 1983 H5N2 outbreak.
Analysis of a large cluster of nonessential genes deleted from a vaccinia virus terminal transposition mutant.
The principal objectives of this study were to analyze the structure and coding potential of a long segment of DNA missing from a previously isolated (B. Moss, E. Winters, and J. A. Cooper (1981) J. Virol. 40, 387-395) attenuated variant of vaccinia virus strain WR and to examine the precise changes in the genome accompanying the deletion. The sequences of a 14.5-kbp region located at the left end of the standard vaccinia virus genome, extending from within the inverted terminal repetition (ITR) of the HindIII C fragment to the end of the HindIII N fragment, and of a 3-kbp segment from a corresponding region of the variant genome were determined. A comparison of these sequences revealed that the variant contained a deletion of 12 kbp and an insertion of 2.1 kbp. The origin of the inserted DNA was traced to the HindIII B region by using oligonucleotide probes indicating that a transposition of unique DNA located adjacent to the right ITR had occurred. Structural analysis indicated no extensive homologies, nucleotide substitutions, additions, or deletions at the boundaries of the transposed DNA. Examination of the right end of the variant genome indicated that a copy of the transposed DNA was still present and, therefore, the length of the ITR had been increased by 2.1 kbp. The variant genome could have formed by a mechanism that resulted in the replacement of a 22-kbp left-terminal fragment with a 12-kbp right-terminal fragment. The DNA missing from the variant and contained within the standard vaccinia virus WR genome contains 17 contiguous open reading frames (ORFs), all of which are directed leftward and apparently not required for replication in cultured cells. One deleted ORF has a 60% sequence similarity to another gene encoding a 42,000-Da protein present within the ITR suggesting that duplications have previously occurred during the evolution of vaccinia virus. Another deleted ORF has a 39% sequence similarity to a complement 4b binding protein. The transposed DNA contains two complete ORFs one of which has a 40% identity to a cowpox gene and a 30% identity to a family of plasma serine protease inhibitors.
[The dynamic ecology of virus-vector system (author's transl)].
The phenomenon of arbovirus transmission by their vectors is based upon the constitution of virus-vector systems, not only at the species level, but also at an infra-specific level. The study of such systems leads to consider some particular aspects of their ecology which can have important epidemiological consequences (selection of viral clones by the vector, transovarial and sexual transmissions). Finely the authors approach the question of evolution of virus-vector systems, which appear as adaptative, functional and temporary associations.
Evolutionarily selected replication origins: functional aspects and structural organization.
A selective replicative pressure occurs during the evolution of simian virus 40 variants. When the replication origin is duplicated as an inverted repeat, there is a dramatic enhancement of replication. Having regulatory sequences located between the inverted repeat of ori magnifies their enhancing effect on replication. A passage 20 variant and a passage 45 variant containing three pairs of an inverted repeat of ori replicated more efficiently than a passage 13 variant containing nine copies of ori arranged in tandem. A 69-base-pair cellular sequence inserted between inverted repeats of ori of both passage 40 and 45 variants enhanced simian virus 40 DNA replication. Differences in replication efficiencies became greater as the total number of replicating species was increased in the transfection mixture, under conditions where T antigen is limiting. In a competitive environment, sequences flanking the replication origin may be inhibitory to replication.
Evolution of the fish rhabdovirus viral haemorrhagic septicaemia virus.
Viral haemorrhagic septicaemia (VHS) caused by the rhabdovirus VHSV is economically the most important viral disease in European rainbow trout farming. Until 1989, this virus was mainly isolated from freshwater salmonids but in the last decade, it has also been isolated from an increasing number of free-living marine fish species. To study the genetic evolution of VHSV, the entire G gene from 74 isolates was analysed. VHSV from wild marine species caught in the Baltic Sea, Skagerrak, Kattegat, North Sea, and English Channel and European freshwater isolates, appeared to share a recent common ancestor. Based on the estimated nucleotide substitution rate, the ancestor of the European fresh water isolates was dated some 50 years ago. This finding fits with the initial reports in the 1950s on clinical observations of VHS in Danish freshwater rainbow trout farms. The study also indicates that European marine VHSV and the North American marine line separated approx. 500 years ago. The codon substitution rate among the freshwater VHSV isolates was found to be 2.5 times faster than among marine isolates. The data support the hypothesis of the marine environment being the original reservoir of VHSV and that the change in host range (to include rainbow trout) may have occurred several times. Virus from the marine environment will therefore continue to represent a threat to the trout aquaculture industry.
Evolution of evolvability.
Genomic sequence data provide evidence for a common origin of life and for its evolution by genetic variation via mutation and recombination. This paper discusses the fundamental dialectic paradigm of evolution--stability versus variability--at the crossroads of molecular genetics, population genetics, ecology, and the emerging science of experimental evolution. Experimental evolution of molecules, viruses, and bacteria can be used not only to test some basic evolutionary hypotheses but also to create new organisms for applications in biotechnology, agriculture, and medicine.