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[Variable mechanisms of RNA-recombination].

Recombination is widespread among RNA viruses but underlying mechanisms remain poorly understood. Until recently, replicative template switching was considered the only possible mechanism of RNA recombination but new evidence suggests that other variants of replicative mechanisms may also exist. In addition, nonreplicative recombination (i.e., joining of preexisting molecules) of genomes of RNA viruses is possible. Recombination is an efficient tool contributing to both variability and stability of the viral RNA genomes. Nonreplicative joining of RNA pieces in the form of trans-splicing is an important physiological mechanism in at least certain organisms. It is conceivable that RNA-recombination has contributed, and perhaps is still contributing, to the evolution of DNA genomes.

Allolevivirus↗
PubMed2003

Transcription strategy in a Closterovirus: a novel 5'-proximal controller element of Citrus Tristeza Virus produces 5'- and 3'-terminal subgenomic RNAs and differs from 3' open reading frame controller elements.

Citrus tristeza virus (CTV) produces more than thirty 3'- or 5'-terminal subgenomic RNAs (sgRNAs) that accumulate to various extents during replication in protoplasts and plants. Among the most unusual species are two abundant populations of small 5'-terminal sgRNAs of approximately 800 nucleotides (nt) termed low-molecular-weight tristeza (LMT1 and LMT2) RNAs. Remarkably, CTV replicons with all 10 3' genes deleted produce only the larger LMT1 RNAs. These 5'-terminal positive-sense sgRNAs do not have corresponding negative strands and were hypothesized to be produced by premature termination during plus-strand genomic RNA synthesis. We characterized a cis-acting element that controls the production of the LMT1 RNAs. Since manipulation of this cis-acting element in its native position (the L-ProI region of replicase) was not possible because the mutations negatively affect replication, a region (5'TR) surrounding the putative termination sites (nt approximately 550 to 1000) was duplicated in the 3' end of a CTV replicon to allow characterization. The duplicated sequence continued to produce a 5'-terminal plus-strand sgRNA, here much larger ( approximately 11 kb), apparently by termination. Surprisingly, a new 3'-terminal sgRNA was observed from the duplicated 5'TR. A large 3'-terminal sgRNA resulting from the putative promoter activity of the native 5'TR was not observed, possibly because of the down-regulation of a promoter approximately 19 kb from the 3' terminus. However, we were able to observe a sgRNA produced from the native 5'TR of a small defective RNA, which placed the native 5'TR closer to the 3' terminus, demonstrating sgRNA promoter activity of the native 5'TR. Deletion mutagenesis mapped the promoter and the terminator activities of the 5'TR (in the 3' position in the CTV replicon) to a 57-nt region, which was folded by the MFOLD computer program into two stem-loops. Mutations in the putative stem-loop structures equally reduced or prevented production of both the 3'- and 5'-terminal sgRNAs. These mutations, when introduced in frame in the native 5'TR, similarly abolished the synthesis of the LMT1 RNAs and presumably the large 3'-terminal sgRNA while having no impact on replication, demonstrating that neither 5'- nor 3'-terminal sgRNA is necessary for replication of the replicon or full-length CTV in protoplasts. Differences between the 5'TR, which produced two plus-strand sgRNAs, and the cis-acting elements controlling the 3' open reading frames, which produced additional minus-strand sgRNAs corresponding to the 3'-terminal mRNAs, suggest that the different sgRNA controller elements had different origins in the modular evolution of closteroviruses.

Base Sequence↗
PubMed2000

Coreceptor usage of HIV-1 isolates representing different genetic subtypes obtained from pregnant Cameroonian women. European Network for In Utero Transmission of HIV-1.

In this study, coreceptor usage of HIV-1 other than subtype B in relation to HIV-1 transmission from mother to child was investigated. Repeated sampling of 42 HIV-1-seropositive, asymptomatic women in Cameroon during the second and third trimesters of pregnancy, at delivery, and 6 months postpartum were performed. Env subtyping was carried out from uncultured peripheral blood mononuclear cells (PBMCs) by heteroduplex mobility assay and, whenever necessary, by DNA sequencing. Virus isolates were tested for coreceptor usage on human cell lines-U87.CD4 and GHOST(3)-engineered to express stably CD4 and the chemokine receptors CCR1, CCR2b, CCR3, CCR5, or CXCR4, or the orphan receptors BOB/gpr15 or Bonzo/STRL33/TYMSTR. Transmission rate was 11.9%. Viruses were predominantly envelope subtype A and used CCR5 as coreceptor and, surprisingly, 4 of 28 (14.2%) isolates from mothers and 1 of 3 isolates from children used the orphan receptor Bonzo as well. In 2 transmitting mothers from whom sequential HIV-1 isolates were available, viral coreceptor usage evolved from CCR5 monotropic to CCR5/Bonzo dual tropic during pregnancy, and in 1 case transmission of this virus could be documented. Our data suggest that evolution of HIV-1 coreceptor usage to dual (or multi-) tropism may occur during pregnancy.

Cameroon↗
PubMed1997

Human immunodeficiency virus type 1 genetic evolution in children with different rates of development of disease.

The rate of development of disease varies considerably among human immunodeficiency virus type 1 (HIV-1)-infected children. The reasons for these observed differences are not clearly understood but most probably depend on the dynamic interplay between the HIV-1 quasispecies virus population and the immune constraints imposed by the host. To study the relationship between disease progression and genetic diversity, we analyzed the evolution of viral sequences within six perinatally infected children by examining proviral sequences spanning the C2 through V5 regions of the viral envelope gene by PCR of blood samples obtained at sequential visits. PCR product DNAs from four sample time points per child were cloned, and 10 to 13 clones from each sample were sequenced. Greater genetic distances relative to the time of infection were found for children with low virion-associated RNA burdens and slow progression to disease relative to those found for children with high virion-associated RNA burdens and rapid progression to disease. The greater branch lengths observed in the phylogenetic reconstructions correlated with a higher accumulation rate of nonsynonymous base substitutions per potential nonsynonymous site, consistent with positive selection for change rather than a difference in replication kinetics. Viral sequences from children with slow progression to disease also showed a tendency to form clusters that associated with different sampling times. These progressive shifts in the viral population were not found in viral sequences from children with rapid progression to disease. Therefore, despite the HIV-1 quasispecies being a diverse, rapidly evolving, and competing population of genetic variants, different rates of genetic evolution could be found under different selective constraints. These data suggest that the evolutionary dynamics exhibited by the HIV-1 quasispecies virus populations are compatible with a Darwinian system evolving under the constraints of natural selection.

Amino Acid Sequence↗
PubMed2002

Evolution of viral structure.

Viruses vastly outnumber their host cells and must present a huge selective pressure. It is also becoming evident that only a small percent of the eukaryotic genome codes for molecules involved in cellular structures and functions, and that much of the remainder may have a viral origin. Viruses clearly play a central role in the biosphere, but how is this viral world organized? Classification was originally based on virus morphology and the particular host infected, but now there is an increasing trend to rely on sequence information. The type of genome (e.g., RNA or DNA, single- or double-stranded) provides fundamental classification criteria, while sequence comparisons can provide fine mapping for closely related viruses. However, it is currently very difficult to identify long-range evolutionary relationships. We present here a different approach, based on the idea that each virus has an innate "self." When the structures and functions characteristic of this "self" are identified, then they uncover relationships beyond those accessible from sequence information alone. The new approach is illustrated by sketching some possible viral lineages. We propose that urviruses were present before the division of cellular life into its current domains, and that the viral world has lineages that can be traced back to the root of the universal tree of life.

Biological Evolution↗
PubMed2000

Evolution of the family of pRN plasmids and their integrase-mediated insertion into the chromosome of the crenarchaeon Sulfolobus solfataricus.

Plasmid pHEN7 from Sulfolobus islandicus was sequenced (7.83 kb) and shown to belong to the archaeal pRN family, which includes plasmids pRN1, pRN2, pSSVx and pDL10 that share a large conserved sequence region. pHEN7 is most closely related to pRN1 in this conserved region. It also shares a large variant region containing several homologous genes with pDL10, which is absent from the other plasmids. The variant region is flanked by the sequence motif TTAGAATGGGGATTC and similar duplicated motifs occur in plasmids pRN1 and pRN2, separated by a few bases. It is inferred that recombination at these sites produces the main genetic variability in the plasmid family. The conserved region of the plasmid, and duplicated copies of the motif, are also present in the genome of Sulfolobus solfataricus P2. Moreover, they are bordered by a partitioned integrase gene (int) and by a 45 bp perfect direct repeat corresponding to the downstream half of a tRNA(Val) gene. The integrase and the direct repeat are highly similar in sequence to the integrase and the chromosomal integration site (att), respectively, of the SSV1 virus, which integrates into the chromosome of Sulfolobus shibatae. Recombination at the att repeats in S. solfataricus would produce a novel plasmid, pXQ1, which carries both an intact integrase gene and a single integration site (att). This strongly suggests that the same mechanism of site-specific integration at a tRNA gene is used for both viruses and plasmids in Sulfolobus.

Attachment Sites, Microbiological↗
PubMed1999

Evolution of the genetic code.

Comparative path lengths in amino acid biosynthesis and other molecular indicators of the timing of codon assignment were examined to reconstruct the main stages of code evolution. The codon tree obtained was rooted in the 4 N-fixing amino acids (Asp, Glu, Asn, Gln) and 16 triplets of the NAN set. This small, locally phased (commaless) code evidently arose from ambiguous translation on a poly(A) collector strand, in a surface reaction network. Copolymerisation of these amino acids yields polyanionic peptide chains, which could anchor uncharged amide residues to a positively charged mineral surface. From RNA virus structure and replication in vitro, the first genes seemed to be RNA segments spliced into tRNA. Expansion of the code reduced the risk of mutation to an unreadable codon. This step was conditional on initiation at the 5'-codon of a translated sequence. Incorporation of increasingly hydrophobic amino acids accompanied expansion. As codons of the NUN set were assigned most slowly, they received the most nonpolar amino acids. The origin of ferredoxin and Gln synthetase was traced to mid-expansion phase. Surface metabolism ceased by the end of code expansion, as cells bounded by a proteo-phospholipid membrane, with a protoATPase, had emerged. Incorporation of positively charged and aromatic amino acids followed. They entered the post-expansion code by codon capture. Synthesis of efficient enzymes with acid-base catalysis was then possible. Both types of aminoacyl-tRNA synthetases were attributed to this stage. tRNA sequence diversity and error rates in RNA replication indicate the code evolved within 20 million yr in the preIsuan era. These findings on the genetic code provide empirical evidence, from a contemporaneous source, that a surface reaction network, centred on C-fixing autocatalytic cycles, rapidly led to cellular life on Earth.

Amino Acids↗
PubMed2001

Diversity, origin, and distribution of retrotransposons (gypsy and copia) in conifers.

We examined the diversity, evolution, and genomic organization of retroelements in a wide range of gymnosperms. In total, 165 fragments of the reverse transcriptase (RT) gene domain were sequenced from PCR products using newly designed primers for gypsy-like retrotransposons and well-known primers for copia-like retrotransposons; representatives of long interspersed nuclear element (LINE) retroposons were also found. Gypsy and copia-like retroelements are a major component of the gymnosperm genome, and in situ hybridization showed that individual element families were widespread across the chromosomes, consistent with dispersion and amplification via an RNA intermediate. Most of the retroelement families were widely distributed among the gymnosperms, including species with wide taxonomic separation from the Northern and Southern Hemispheres. When the gymnosperm sequences were analyzed together with retroelements from other species, the monophyletic origin of plant copia, gypsy, and LINE groups was well supported, with an additional clade including badnaviral and other, probably virus-related, plant sequences as well as animal and fungal gypsy elements. Plant retroelements showed high diversity within the phylogenetic trees of both copia and gypsy RT domains, with, for example, retroelement sequences from Arabidopsis thaliana being present in many supported groupings. No primary branches divided major taxonomic clades such as angiosperms, monocotyledons, gymnosperms, or conifers or (based on smaller samples) ferns, Gnetales, or Sphenopsida (Equisetum), suggesting that much of the existing diversity was present early in plant evolution, or perhaps that horizontal transfer of sequences has occurred. Within the phylogenetic trees for both gypsy and copia, two clearly monophyletic gymnosperm/conifer clades were revealed, providing evidence against recent horizontal transfer. The results put the evolution of the large and relatively conserved genome structure of gymnosperms into the context of the diversity of other groups of plants.

Animals↗
PubMed2002

Discontinuous and non-discontinuous subgenomic RNA transcription in a nidovirus.

Arteri-, corona-, toro- and roniviruses are evolutionarily related positive-strand RNA viruses, united in the order Nidovirales. The best studied nidoviruses, the corona- and arteriviruses, employ a unique transcription mechanism, which involves discontinuous RNA synthesis, a process resembling similarity-assisted copy-choice RNA recombination. During infection, multiple subgenomic (sg) mRNAs are transcribed from a mirror set of sg negative-strand RNA templates. The sg mRNAs all possess a short 5' common leader sequence, derived from the 5' end of the genomic RNA. The joining of the non-contiguous 'leader' and 'body' sequences presumably occurs during minus-strand synthesis. To study whether toroviruses use a similar transcription mechanism, we characterized the 5' termini of the genome and the four sg mRNAs of Berne virus (BEV). We show that BEV mRNAs 3-5 lack a leader sequence. Surprisingly, however, RNA 2 does contain a leader, identical to the 5'-terminal 18 residues of the genome. Apparently, BEV combines discontinuous and non-discontinuous RNA synthesis to produce its sg mRNAs. Our findings have important implications for the understanding of the mechanism and evolution of nidovirus transcription.

Base Sequence↗
PubMed1995

Nucleotide sequence and protein analysis of a complex piscine retrovirus, walleye dermal sarcoma virus.

Walleye dermal sarcoma virus (WDSV) is a fish retrovirus associated with the development of tumors in walleyes. We have determined the complete nucleotide sequence of a DNA clone of WDSV, the N-terminal amino acid sequences of the major proteins, and the start site for transcription. The long terminal repeat is 590 bp in length, with the U3 region containing consensus sequences likely to be involved in viral gene expression. A predicted histidyl-tRNA binding site is located 3 nucleotides distal to the 3' end of the long terminal repeat. Virus particles purified by isopycnic sedimentation followed by rate zonal sedimentation showed major polypeptides with molecular sizes of 90, 25, 20, 14, and 10 kDa. N-terminal sequencing of these allowed unambiguous assignment of the small polypeptides as products of the gag gene, including CA and NC, and the large polypeptide as the TM product of env. The 582-amino-acid (aa) Gag protein precursor is predicted to be myristylated as is found for most retroviruses. NC contains a single Cys-His motif like those found in all retroviruses except spumaviruses. The WDSV pro and pol genes are in the same translational reading frame as gag and thus apparently are translated after termination suppression. The env gene encodes a surface (SU) protein of 469 aa predicted to be highly glycosylated and a large transmembrane (TM) protein of 754 aa. The sequence of TM is unusual in that it ends in a very hydrophobic segment of 65 residues containing a single charged residue. Following the env gene are two nonoverlapping long open reading frames of 290 aa (orf-A) and 306 aa (orf-B), neither of which shows significant sequence similarity with known genes. A third open reading frame of 119 aa (orf-C) is located in the leader region preceding gag. The predicted amino acid sequence of reverse transcriptase would place WDSV phylogenetically closest to the murine leukemia virus-related genus of retroviruses. However, other members of this genus do not have accessory genes, suggesting that WDSV acquired orf-A, orf-B, and perhaps orf-C late in its evolution. We hypothesize by analogy with other complex retroviruses that the accessory genes of WDSV function in the regulation of transcription and in RNA processing and also in the induction of walleye dermal sarcoma.

Amino Acid Sequence↗
PubMed1996

Rapid evolution of human immunodeficiency virus strains with increased replicative capacity during the seronegative window of primary infection.

The relationship between host and virus was examined during the initial stages of human immunodeficiency virus type 1 (HIV) infection in a volunteer from the Multicenter AIDS Cohort Study (MACS). The individual was asymptomatic and unaware of his infection during an initial donation of blood and inguinal lymphoid tissue. Proviral DNA, however, was present in cells from both sources, HIV RNA was detected in the plasma, and CD4+ cell levels were reduced by approximately 50% compared with previous donations in the MACS. In a second blood donation 12 days later, plasma HIV RNA increased 200-fold in tandem with viral isolates with an increased growth phenotype in vitro. HIV burden was ultimately suppressed upon seroconversion and the emergence of HIV-specific CD8+ cytotoxic T lymphocytes. These observations provide further evidence that the potential benefits of early treatment may be maximized during the early stages of infection, when viral fitness may be low but is unopposed by immune responses.

CD4-Positive T-Lymphocytes↗
PubMed2000

Hepatitis C virus RNA codes for proteins and replicates: does it also trigger the interferon response?

Hepatitis C virus (HCV) is a positive sense virus with a genomic RNA molecule roughly 9,600 nucleotides in length. The single-stranded genomic RNA has a nontranslated region (NTR) at each end and a long open reading frame (coding region) in between. The 5'NTR and portions of the 3'NTR are the most conserved parts of HCV RNA. These conserved regions contain signals for replication and translation. Much of the 5'NTR is folded into a structure that binds ribosomes. This structure, an internal ribosome entry site, promotes the initiation of protein synthesis and is critical for HCV gene expression. The ribosome binding site may extend into the coding region; its exact boundaries are not known. The open reading frame encodes the HCV polyprotein, which is slightly more than 3,000 amino acids in length. The 3'NTR plays a key role in HCV replication and may also influence the rate of HCV protein synthesis. During replication, the genomic RNA is copied by virally encoded enzymes into a complementary antigenomic RNA, which itself is a template for the synthesis of progeny RNAs. At steady state, genomic strands outnumber antigenomic strands about 10 to 1. HCV RNA replication is thought to take place in the cytoplasm and is an error-prone process. It generates a mixed population of RNA sequences (quasispecies), including mutants that may be more fit than the parental type, less fit, or equally fit (but distinct). Natural selection acts upon the progeny RNAs, causing the population to change and drift. Over time, mutation, selection, and population bottlenecks led to the evolution of varied genotypes. The HCV replication complex is a potential source of double-stranded RNA, a powerful inducer of interferon. Thus, HCV-specific double-stranded RNA may trigger the first steps of innate immunity; however, for unknown reasons, the immune system often fails to clear the infection. The plasticity of the HCV genome and the low level of HCV gene expression may counterbalance any immunostimulatory effects of HCV RNA and allow the virus to escape specific immune responses. Antisense drugs and ribozymes directed against HCV RNA are under investigation. Future interventions may include nucleic acid drugs (antisense and ribozymes) and smaller pharmaceuticals that bind to intricate structures in HCV RNA and HCV-specific double-stranded RNA. Infectious clones of HCV RNA are available. These clones and other systems for expressing HCV proteins pave the way for vaccine development.

Genes, Viral↗
PubMed1989

Physical map of the genome of sonchus yellow net virus, a plant rhabdovirus with six genes and conserved gene junction sequences.

We provide evidence that a plant rhabdovirus, sonchus yellow net virus (SYNV), is similar to most animal rhabdoviruses in the order of structural genes and in the nucleotide sequences at the gene junctions but that it differs in the presence and location of a putative nonstructural gene. From the patterns of hybridization of a library of recombinant DNA clones, we have shown that the SYNV genome is transcribed into a short 3'-terminal "leader RNA" and six mRNAs. The proteins encoded by the SYNV mRNAs, in order of the appearance of their genes in the SYNV genome, are designated 3'-N-M2-sc4-M1-G-L-5' (N, nucleoprotein; M, matrix protein; sc, protein encoded by SYNV complementary RNA; G, glycoprotein; L, large protein). The intergenic and flanking gene sequences are conserved and consist of a central core of 14 nucleotides (3'-UUCUUUUUGGUUGU/A-5') whose sequence is similar to the sequence at the gene junctions of vesicular stomatitis and rabies viruses. The SYNV core consists of an 8-nucleotide (3'-UUCUUUUU-5') transcription termination signal at the 5' terminus of each gene, a dinucleotide (GG) spacer whose complement does not appear in mRNA, and a tetranucleotide (3'-UUGU/A-5') that is complementary to the first four nucleotides at the 5' terminus of the SYNV mRNAs. These results, when compared with structural information available on animal rhabdoviruses, suggest that organization of structural genes and maintenance of signals thought to play important roles in regulation of transcription have been conserved during evolution in plant, insect, and vertebrate hosts. However, differences in number and location of putative nonstructural genes reveal some flexibility in genome organization that may be important in deducing taxonomic and evolutionary relationships among viruses causing diseases in phylogenetically diverse hosts.

Base Sequence↗
PubMed1993

Genetic analysis of the cofactor requirement for human immunodeficiency virus type 1 Tat function.

The Tat protein of human immunodeficiency virus type 1 is a potent transcriptional trans activator of the viral long terminal repeat promoter element. Tat function requires the direct interaction of Tat with a cis-acting viral RNA target sequence termed the trans-activation response (TAR) element and has also been proposed to require at least one cellular cofactor. We have used a genetic approach to attempt to experimentally define the role of the cellular cofactor in Tat function and TAR binding. Our data suggest that neither Tat nor the cellular cofactor binds to TAR alone in vivo and indicate, instead, that the interaction of Tat with its cellular cofactor is a prerequisite for TAR binding. The known species tropism of lentivirus Tat proteins appears to arise from the fact that not only Tat but also the cellular cofactor can markedly influence the RNA sequence specificity of the resultant protein complex. These data also suggest that the Tat cofactor is likely a cellular transcription factor that has been highly conserved during vertebrate evolution. We hypothesize that the primary function of Tat is to redirect this cellular factor to a novel viral RNA target site and to thereby induce activation of viral gene expression.

Amino Acid Sequence↗
PubMed1993

Multiple coding and the evolutionary properties of RNA secondary structure.

This article evaluates evolutionary properties of the transition from RNA primary sequence to RNA secondary structure. It focuses on the restrictions that the conservation of a protein code in an RNA sequence puts on its potential to evolve towards a specific secondary structure. Restricting the mutations to those that do not affect the coding for a protein restricts both the accessibility and the connectivity of the sequence space. The accessibility is restricted because only certain point mutations are allowed. The connectivity is restricted because no insertions and deletions are allowed. Simulating an evolutionary search process for a specific secondary structure shows that (i) the reduction of allowable point mutations allows for adaptation to some large-scale topology, but strongly reduces the possibility of small-scale adaptations, (ii) the abolition of insertions and deletions has very little effect on the results of the search process. During the evolutionary search process for a secondary structure with a specific topology and a high frequency of base-pairing the quasispecies moves into a subspace in which the similarity between secondary structures of neighboring sequences is relatively high. Increased similarity between second structures of neighboring sequences is also found in the Rev responsive element (RRE) in the lentiviruses Caprine arthritis-encephalitis virus and Visna virus. In these viruses a biased nucleotide frequency in the RRE region suggests that selection for the RRE RNA secondary structure affects the amino acid sequence of the env gene. Our results show a variation in the ruggedness of fitness landscapes which are based on a high degree of epistatic interactions. Fitness landscapes play an essential role, not only in biotic evolution, but also in all kinds of optimization processes (Hill Climbing, Simulated Annealing, Genetic Algorithms, etc). Variation in their ruggedness should therefore be taken into account in the analysis of these processes.

Amino Acid Sequence↗
PubMed1982

Transforming gene of a human leukaemia cell is unrelated to the expressed tumour virus related gene of the cell.

The virally encoded oncogenes (v-onc) of avian and mammalian retroviruses are the recombinant products of normal cellular genes (c-onc) and a retroviral genome. These cellular homologues have been highly conserved during evolution and are found in human DNA. The expression of at least one c-onc under the control of a viral promoter results in transformation of cells in a manner resembling that displayed by the v-onc counterpart; the inappropriate expression of c-onc in the absence of viral influences could likewise result in the malignant state. This proposal would be strongly supported by the presence of c-onc RNAs in a variety of human tumours were they not also demonstrable in normal tissues. The role of these RNAs in the oncogenic process remains unclear. Here we report that RNA homologous to the oncogene (v-abl) of Abelson murine leukaemia virus (A-MLV) is expressed in a unique human leukaemia in a fashion different from that of other human tissues and tumours. In addition, DNA from this tumour transforms NIH-3T3 cells at a high efficiency in a transfection assay. The transfected sequences are not related to the v-abl gene, but the NIH-3T3 transformants manufacture a transforming growth factor which behaves similarly to factors produced by A-MLV-transformed NIH-3T3 fibroblasts.

Abelson murine leukemia virus↗