Genomic divergence among Sindbis virus strains.
Explore the source record for details and available documents.
SEARCH · Search PubMed
Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
Explore the source record for details and available documents.
Much of the worlds' population is in active or imminent danger from established infectious pathogens, while sporadic and pandemic infections by these and emerging agents threaten everyone. RNA polymerases (RNApol) generate enormous genetic and consequent antigenic heterogeneity permitting both viruses and cellular pathogens to evade host defences. Thus, RNApol causes more morbidity and premature mortality than any other molecule. The extraordinary genetic heterogeneity defining viral quasispecies results from RNApol infidelity causing rapid cumulative genomic RNA mutation a process that, if uncontrolled, would cause catastrophic loss of sequence integrity and inexorable quasispecies extinction. Selective replication and replicative homeostasis, an epicyclical regulatory mechanism dynamically linking RNApol fidelity and processivity with quasispecies phenotypic diversity, modulating polymerase fidelity and, hence, controlling quasispecies behaviour, prevents this happening and also mediates immune escape. Perhaps more importantly, ineluctable generation of broad phenotypic diversity after viral RNA is translated to protein quasispecies suggests a mechanism of disease that specifically targets, and functionally disrupts, the host cell surface molecules--including hormone, lipid, cell signalling or neurotransmitter receptors--that viruses co-opt for cell entry. This mechanism--"Viral Receptor Disease (VRD)"--may explain so-called "viral autoimmunity", some classical autoimmune disorders and other diseases, including type II diabetes mellitus, and some forms of obesity. Viral receptor disease is a unifying hypothesis that may also explain some diseases with well-established, but multi-factorial and apparently unrelated aetiologies--like coronary artery and other vascular diseases--in addition to diseases like schizophrenia that are poorly understood and lack plausible, coherent, pathogenic explanations.
Viruses, especially those with RNA genomes, represent ideal organisms to study the dynamics of microevolutionary change. In particular, their rapid rate of nucleotide substitution means that the epidemiological processes that shape their diversity act on the same time-scale as mutations are fixed in viral populations. Consequently, the branching structure of virus phylogenies provides a unique insight into spatial and temporal dynamics. Herein, I describe the key processes in virus phylogeography. These are generally associated with the relative rates of dispersal among populations and virus-host codivergence (vicariance), and the division between acute (short-term) and persistent (long-term) infections. These processes will be illustrated by important human viruses - HIV, dengue, rabies, polyomavirus JC and human papillomavirus - which display varying spatial and temporal structures and virus-host relationships. Key research questions for the future will also be established.
HIV-1 RNA levels in semen and blood compartments decrease below detection limits during highly active antiretroviral therapy. Despite these therapeutic effects, it is clear that persistent, latent HIV-1 reservoirs are capable of rebounding in the absence of drug treatment or by evolution of escape mutants remain. The current study was designed to examine the presence of latent virus in semen and blood compartments and its evolution following potent combination therapy with indinavir (protease inhibitor) and efavirenz [nonnucleoside reverse transcriptase (RT) inhibitor]. Using an ultrasensitive in situ hybridization assay HIV-1 mRNA was detected in cultured seminal and blood mononuclear cells in all patients up to 1789 days posttherapy. Higher levels of HIV-1 mRNA were consistently detected in seminal mononuclear cells as compared to peripheral blood mononuclear cells (PBMC) in all time points analyzed posttherapy. Analysis of viral RNA from cultured PBMC before and after therapy displayed no evidence of therapy-induced drug resistance in the viral polymerase gene in the majority of patients. However, distinct envelope populations were detected in these viral RNA populations following therapy, indicating possible selection of quasispecies. The observed ongoing replication and evolution in the PBMC viral envelope sequences likely occurred in the seminal compartment HIV populations, given that the seminal cells showed the ability to express HIV-1 mRNA following cultivation. This together with our previous studies (Gupta P, et al.: J Infect Dis 2000;182:79-87) suggest that the genital and blood compartments likely serve as distinct reservoirs harboring latent HIV-1 during prolonged drug therapy.
The evolution over the past century of two tobamoviruses infecting populations of the immigrant plant Nicotiana glauca in New South Wales (NSW), Australia, has been studied. This plant species probably entered Australia in the 1870s. Isolates of the viruses were obtained from N. glauca specimens deposited in the NSW Herbarium between 1899 and 1972, and others were obtained from living plants in 1985 and 1993. It was found that the NSW N. glauca population was infected with tobacco mosaic tobamovirus (TMV) and tobacco mild green mosaic tobamovirus (TMGMV) before 1950 but only with TMGMV after that date. Half the pre-1950 infections were mixtures of the two viruses, and one was a recombinant. Remarkably, sequence analyses showed no increase in the genetic diversity among the TMGMV isolates over the period. However, for TMV, the genetic diversity of synonymous (but not of nonsynonymous) differences between isolates varied and was correlated with their time of isolation. TMV accumulated to smaller concentrations than TMGMV in N. glauca plants, and in mixed experimental infections, the accumulation of TMV, but not of TMGMV, was around 1/10 that in single infections. However, no evidence was found of isolate-specific interaction between the viruses. We conclude that although TMV may have colonized N. glauca in NSW earlier or faster than TMGMV, the latter virus caused a decrease of the TMV population below a threshold at which deleterious mutations were eliminated. This phenomenon, called Muller's ratchet, or a "mutational meltdown," probably caused the disappearance of TMV from the niche.
Explore the source record for details and available documents.
Some strains of the protozoan parasite Leishmania belonging to the new world species guyanensis and braziliensis are infected with persistent, single-segmented, non-enveloped dsRNA viruses termed LRV1. A single old world strain classified as L. major was recently found to harbor a similar virus, designated LRV2-1. The genomic nucleotide sequences of two LRV1 types (1-1 and 1-4) isolated from two L. guyanensis strains have been determined and found to be highly conserved. In contrast, LRV1-specific cDNA probes derived from the conserved genomic 5' region failed to recognize LRV2 RNA on Northern blots, suggesting a greater degree of divergence between LRV1 and LRV2 than among LRV1 types. This observation suggests a long-term association and coevolution of LRV within each parasite strain. We tested this concept by comparing nucleotide sequences of seven LRV types and PCR fingerprints of the parasite strains from which these viruses were derived. In support of the idea of virus-parasite co-evolution, we find that genetic distances between LRV types mirror the heterogeneity between parasite fingerprints and are clustered according to the geographical origin of the strains. In agreement with the postulated common origin of persistent dsRNA viruses of protozoa and fungi, we conclude that the infection of Leishmania with LRV pre-dates the divergence of Leishmania into different lineages.
The entire RNA 3 (2214 nucleotides) of a chrysanthemum isolate of tomato aspermy virus (C-TAV) has been cloned and its sequence determined. C-TAV possesses two open reading frames which encode a 3a protein (277 amino acids) and a coat protein (229 amino acids). Computer-assisted comparisons were made between C-TAV RNA 3 and its predicted protein sequences and those of two other tripartite RNA viruses, cucumber mosaic virus (CMV) and brome mosaic virus (BMV). Results from this study suggest that a close evolutionary relationship exists between C-TAV, Q-CMV and BMV. Divergence of nucleotide and amino acid sequences between these viruses is not reflected at the level of the predicted secondary structure of the encoded proteins, where conservation is strong.
The operator hairpin ahead of the replicase gene in RNA bacteriophage MS2 contains overlapping signals for binding the coat protein and ribosomes. Coat protein binding inhibits further translation of the gene and forms the first step in capsid formation. The hairpin sequence was partially randomized to assess the importance of this structure element for the bacteriophage and to monitor alternative solutions that would evolve on the passaging of mutant phages. The evolutionary reconstruction of the operator failed in the majority of mutants. Instead, a poor imitation developed containing only some of the recognition signals for the coat protein. Three mutants were of particular interest in that they contained double nonsense codons in the lysis reading frame that runs through the operator hairpin. The simultaneous reversion of two stop codons into sense codons has a very low probability of occurring. Therefore the phage solved the problem by deleting the nonsense signals and, in fact, the complete operator, except for the initiation codon of the replicase gene. Several revertants were isolated with activities ranging from 1% to 20% of wild type. The operator, long thought to be a critical regulator, now appears to be a dispensable element. In addition, the results indicate how RNA viruses can be forced to step back to an attenuated form.
The nucleotide sequence of the complete genomes of two Indian isolates of Japanese encephalitis virus were compared. One of these isolates, GP78 was obtained from northern India in 1978. The other, the Vellore P20778 isolate, was obtained from southern India in 1958. There was 4.40% nucleotide sequence divergence between the two Indian isolates that resulted in a 1.86% amino acid sequence divergence. Phylogenetic analyses showed that in evolutionary terms the north Indian GP78 isolate was close to the SA14 isolate from China whereas the south Indian Vellore P20778 isolate was close to the Beijing-1 isolate, also from China. The two Indian isolates, however, appear to have evolved independently.
Explore the source record for details and available documents.
Two flavivirus-like viruses, GB virus-A (GBV-A) and GB virus-B (GBV-B), were recently identified in the GB hepatitis agent, and are distinct from the hepatitis A to E viruses. The putative helicase domain of GBV-A and GBV-B was found to have amino acid sequence homology with hepatitis C virus (HCV), and distantly, is also related to pestiviruses, flaviviruses, and plant viruses. A phylogenetic tree construction showed that GBVs and HCV are closely related, and they are clustered with pestiviruses, flaviviruses and plant viruses in that order.
Explore the source record for details and available documents.
The molecular epidemiology of Bluetongue virus serotype 11 (BTV11) in an enzootic focus in northern Colorado was investigated. Viruses isolated up to 12 years apart, from both vertebrate and invertebrate hosts, were compared by phylogenetic analysis of nucleotide sequence data from three genome segments: L2, S7, and S10. For each segment, viruses isolated from ruminants in the 1980s were more similar to one another than to viruses isolated from Culicoides spp. insects in the 1990s. Nearly identical BTV11-L2 segments were found in all isolates, but over time they were associated with different S7 and S10 genome segments. Therefore, L2-segment-based serologic identification of BTV isolates underestimates the origin and natural evolution of the viruses. In addition, the use of one or even two genome segments is inadequate to define the molecular epidemiology of the viruses in an enzootic focus. This information could influence import/export regulations based on BTV epidemiology in enzootic areas, as well as our view of the natural biology of the viruses.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
Whenever an asexual viral population evolves by adapting to new environmental conditions, beneficial mutations, the ultimate cause of adaptation, are randomly produced and then fixed in the population. The larger the population size and the higher the mutation rate, the more beneficial mutations can be produced per unit time. With the usually high mutation rate of RNA viruses and in a large enough population, several beneficial mutations could arise at the same time but in different genetic backgrounds, and if the virus is asexual, they will never be brought together through recombination. Thus, the best of these genotypes must outcompete each other on their way to fixation. This competition among beneficial mutations has the effect of slowing the overall rate of adaptation. This phenomenon is known as clonal interference. Clonal interference predicts a speed limit for adaptation as the population size increases. In the present report, by varying the size of evolving vesicular stomatitis virus populations, we found evidence clearly demonstrating this speed limit and thus indicating that clonal interference might be an important factor modulating the rate of adaptation to an in vitro cell system. Several evolutionary and epidemiological implications of the clonal interference model applied to RNA viruses are discussed.