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PubMed2026

Creating bottom-up RNA transfer vehicles from synthetic protein assemblies.

Evolution guides biological systems to populate ecological niches, with viruses among the most successful examples of this principle. Viruses evolved over billions of years to efficiently transfer genetic information. Although viruses are highly diverse, most have converged towards remarkable similarity in the size and shape of their capsids1,2. By contrast, generative models for protein design enable the creation of protein architectures that are absent from nature3-5. Here we investigate whether protein assemblies designed by artificial intelligence can be functionalized to construct nucleic acid transport vehicles that are independent of evolutionary trajectories. By combining natural protein domains with synthetic protein assemblies, we create more than 100 bottom-up RNA transfer vehicles with unique sizes and shapes. These vehicles surpass the RNA transfer efficiency of widely used delivery vehicles by several orders of magnitude. In addition, we demonstrate that their tropism can be programmed by incorporation of computationally designed peptide binders and use them to deliver therapeutically relevant cargo RNAs into a wide range of cellular models. We show the in vivo biodistribution of one of these vehicles in a mouse at near-single-cell resolution, confirm its safety, and use it to perform a gene-editing treatment strategy for Duchenne muscular dystrophy in patient-derived cells and a pig. Our work demonstrates how proteins created by generative artificial intelligence can be harnessed for the rational engineering of RNA transport systems with the desired properties by overcoming the limitations of natural protein diversity.

Journal Article↗
PubMed1979

Evolution of human influenza A viruses in nature: recombination contributes to genetic variation of H1N1 strains.

In June of 1977, a new influenza A pandemic was started by strains of the H1N1 serotype. Oligonucleotide fingerprint analysis of the RNA from viruses isolated during the early stage of this pandemic demonstrated that genetic variation among these 1977 strains could be attributed to sequential mutation [Young, J.F., Desselberger, U. & Palese, P. (1979) Cell, 18, 73-83]. Examination of more recent strains revealed that the H1N1 variants that were isolated in the winter of 1978-1979 differed considerably from the H1N1 viruses isolated the previous year. Oligonucleotide and peptide map analysis of the new prototype strain (A/Cal/10/78) suggested that it arose by recombination. It appears that only the HA, NA, M, and NS genes of this virus are derived from the earlier H1N1 viruses and that the P1, P2, P3, and NP genes most likely originate from an H3N2 parent. These data suggest that genetic variation in influenza virus strains of the same serotype is not restricted to mutation alone, but can also involve recombination (reassortment).

Antigens, Viral↗
PubMed1995

Molecular evolution of influenza viruses.

There are two different mechanisms by which influenza viruses might evolve: (1) Because the RNA genome of influenza viruses is segmented, new strains can suddenly be produced by reassortment, as happens, for example, during antigenic shift, creating new pandemic strains. (2) New viruses evolve relatively slowly by stepwise mutation and selection, for example, during antigenic or genetic drift. Influenza A viruses were found in various vertebrate species, where they form reservoirs that do not easily mix. While human influenza A viruses do not spread in birds and vice versa, the species barrier to pigs is relatively low, so that pigs might function as "mixing vessels" for the creation of new pandemic reassortants in Southeast Asia, where the probability is greatest for double infection of pigs by human and avian influenza viruses. Phylogenetic studies revealed that about 100 years ago, an avian influenza A virus had crossed the species barrier, presumably first to pigs, and from there to humans, forming the new stable human and classical swine lineages. In 1979, again, an avian virus showed up in the North European swine population, forming another stable swine lineage. The North European swine isolates from 1979 until about 1985 were genetically extremely unstable. A hypothesis is put forward stating that a mutator mutation is necessary to enable influenza virus to cross the species barrier by providing the new host with sufficient variants from which it can select the best fitting ones. As long as the mutator mutation is still present, such a virus should be able to cross the species barrier a second time, as happened about 100 years ago. Although the most recent swine isolates from northern Germany are again genetically stable, we nevertheless should be on the lookout to see if a North European swine virus shows up in the human population in the near future.

Animals↗
PubMed2004

Transmission cycles, host range, evolution and emergence of arboviral disease.

Many pandemics have been attributed to the ability of some RNA viruses to change their host range to include humans. Here, we review the mechanisms of disease emergence that are related to the host-range specificity of selected mosquito-borne alphaviruses and flaviviruses. We discuss viruses of medical importance, including Venezuelan equine and Japanese encephalitis viruses, dengue viruses and West Nile viruses.

Alphavirus↗
PubMed1978

Common sequence at the 5' ends of the segmented RNA genomes of influenza A and B viruses.

Guanylyl- and methyltransferases, isolated from purified vaccinia virus, were used to specifically label the 5' ends of the genome RNAs of influenza A and B viruses. All eight segments were labeled with [alpha-(32)P]guanosine 5'-triphosphate or S-adenosyl[methyl-(3)H]methionine to form "cap" structures of the type m(7)G(5')pppN(m)-, of which unmethylated (p)ppN- represents the original 5' end. Further analyses indicated that m(7)G(5')pppA(m), m(7)G(5')pppA(m)pGp, and m(7)G(5')pppA(m)pGpUp were released from total and individual labeled RNA segments by digestion with nuclease P1, RNase T1, and RNase A, respectively. Consequently, the 5'-terminal sequences of most or all individual genome RNAs of influenza A and B viruses were deduced to be (p)ppApGpUp. The presence of identical sequences at the ends of RNA segments of both types of influenza viruses indicates that they have been specifically conserved during evolution.

Base Sequence↗
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↗
PubMed2006

Transitions in understanding of RNA viruses: a historical perspective.

This chapter documents that RNA viruses have been known for over a century to be genetically variable. In recent decades, genetic and molecular analyses demonstrate that they form RNA quasispecies populations; the most rapidly mutating, highly variable and genetically versatile life forms on earth. Their enormous populations, rapid replication and extreme genetic plasticity can allow rates of evolution that exceed those of their eukaryotic host populations by millions-fold.

Evolution, Molecular↗
PubMed2006

Comparative and functional genomics of closteroviruses.

The largest extant RNA genomes are found in two diverse families of positive-strand RNA viruses, the animal Coronaviridae and the plant Closteroviridae. Comparative analysis of the viruses from the latter family reveals three levels of gene conservation. The most conserved gene module defines RNA replication and is shared with plant and animal viruses in the alphavirus-like superfamily. A module of five genes that function in particle assembly and transport is a hallmark of the family Closteroviridae and was likely present in the ancestor of all three closterovirus genera. This module includes a homologue of Hsp70 molecular chaperones and three diverged copies of the capsid protein gene. The remaining genes show dramatic variation in their numbers, functions, and origins among closteroviruses within and between the genera. Proteins encoded by these genes include suppressors of RNA silencing, RNAse III, papain-like proteases, the AlkB domain implicated in RNA repair, Zn-ribbon-containing protein, and a variety of proteins with no detectable homologues in the current databases. The evolutionary processes that have shaped the complex and fluid genomes of the large RNA viruses might be similar to those that have been involved in evolution of genomic complexity in other divisions of life.

Amino Acid Sequence↗
PubMed2003

Identification of RNA ligands that bind hepatitis C virus polymerase selectively and inhibit its RNA synthesis from the natural viral RNA templates.

To identify the potential RNA inhibitors of HCV polymerase, we have isolated high-affinity RNA ligands specific to hepatitis C virus (HCV) NS5B protein from a combinatorial RNA library using the Systematic Evolution of Ligands by EXponential enrichment (SELEX) procedure. Thirty-seven selected ligands were classified into eight groups on the basis of their sequence homologies. Most (60%) of the ligands carry the conserved YGUAGR hexamer (Y = pyrimidine, R = purine) at the 5' end of the 40-nt randomized region, and 74% of the ligands end in (A/C)U at the 3'end. However, strong binding to NS5B required the whole RNA ligand including the flanking conserved nucleotides at both ends. The binding of the selected ligands to NS5B is highly specific and strong, as reflected in their low dissociation rate constants (k(d) approximately 10(-4) s(-1)). Analysis of secondary structure by computer program and RNase footprints of the two different aptamers from two most conserved groups revealed RNA structures containing three stem loops with internal bulges. NS5B bound these RNA at a region between the two stem loops from the 5' -end. Some of these RNA aptamers could serve as a template for the HCV polymerase, but some interfered with the activity of the viral enzyme. These RNA ligands will be useful for further characterization of NS5B-binding properties and, with further modifications, may have potential therapeutic value.

Base Sequence↗
PubMed2005

RNA viruses as complex adaptive systems.

RNA viruses have high mutation rates and so their populations exist as dynamic and complex mutant distributions. It has been consistently observed that when challenged with a new environment, viral populations adapt following hyperbolic-like kinetics: adaptation is initially very rapid, but then slows down as fitness reaches an asymptotic value. These adaptive dynamics have been explained in terms of populations moving towards the top of peaks on rugged fitness landscapes. Fitness fluctuations of varying magnitude are observed during adaptation. Often the presence of fluctuations in the evolution of physical systems indicates some form of self-organization, or where many components of the system are simultaneously involved. Here we analyze data from several in vitro evolution experiments carried out with vesicular stomatitis virus (VSV) looking for the signature of criticality and scaling. Long-range fitness correlations have been detected during the adaptive process. We also found that the magnitude of fitness fluctuations, far from being trivial, conform to a Weibull probability distribution function, suggesting that viral adaptation belongs to a broad category of phenomena previously documented in other fields and related with emergence.

Biological Evolution↗
PubMed2005

A multigene analysis of the phylogenetic relationships among the flaviviruses (Family: Flaviviridae) and the evolution of vector transmission.

The genus Flavivirus (family Flaviviridae) presently comprises around 70 single-strand positive-sense RNA viruses. These replicate in a range of vertebrate and invertebrate cells and may be mosquito-borne, tick-borne or have no-known-vector. Since transmission mode correlates strongly with phylogeny, the flaviviruses constitute a valuable model for the evolution of vector-borne disease. Attempts to resolve the higher-level taxonomic relationships of the flaviviruses through molecular phylogenetics have thus far proved inconclusive because of conflicting positions for the three main transmission groups. We conducted the most comprehensive phylogenetic study to date, involving maximum likelihood analyses of the NS3 and NS5 genes and the entire genome sequences available at present. For the first time, we use and test a variety of more robust methods of sequence alignment and appropriate models of amino acid replacement to study these highly divergent sequences, and explicitly test specific hypotheses of tree topology. We show that (i) the NS5 gene contains insufficient phylogenetic signal to choose between competing topological hypotheses, (ii) the NS3 gene and whole genome data indicate that the mosquito-borne flaviviruses represent an outgroup to the remaining flaviviruses, and (iii) that tick-borne transmission is probably a derived trait within the genus.

Animals↗
PubMed2002

Molecular characterization of rabies virus isolates from Trinidad.

Bovine rabies continues to be a serious problem facing the cattle industry in South and Central America. Although Trinidad played an important role in originally demonstrating the link between bats and bovine rabies, relatively little is known about rabies in Trinidad, an island 7miles off the coast of Venezuela. In order to obtain a more complete understanding of bovine rabies in the region, we report herein on a study undertaken in Trinidad to characterize isolates of rabies virus obtained from infected cattle. A portion of the nucleotide sequence of the nucleoprotein gene from six rabies virus isolates collected from bovine rabies from the years 1997, 1998 and 2000 was determined and compared both to themselves and the nucleotide sequence of other South American isolates. Results indicate that there are at least two independently evolving variants of rabies virus in Trinidad. The nucleotide sequence of either variant failed to match completely the sequence of South American isolates. However, the lack of South American isolates from coastal regions facing Trinidad leaves undetermined the question of South American influence on rabies in Trinidad. The results of this study helps complete the picture of bovine rabies in the South American region and provide basic information required locally for the creation of an effective rabies control and eradication strategy.

Animals↗
PubMed2006

Evolution of SIV envelope in morphine-dependent rhesus macaques with rapid disease progression.

Three morphine-dependent rhesus macaques that developed accelerated AIDS after virus inoculation, along with three control macaques, were followed for evolution of the SIV/17E-Fr envelope. Viral RNA was isolated from plasma samples collected at weeks 6, 12, and 20 postinfection. A 482-nucleotide fragment in the viral env was amplified and cloned into a pCR2.1-TOPO vector. Between 5 and 10 clones were sequenced at each time point from individual monkeys. The sequence analysis showed more mutations in the control animals compared to those seen in the morphine-dependent animals. The virus at different points did not separate completely in phylogenetic analysis. However, the phylogenetic clustering was more apparent in the control animals. Viral diversity and divergence were significantly higher in the control animals. The control animals lost N-glycosylation sites more rapidly. These results suggest that morphine dependence diminished virus evolution in SHIV/SIV-infected rhesus macaques and there was an inverse correlation between virus evolution and onset of clinical disease.

Amino Acid Sequence↗
PubMed2006

Double-stranded RNA and antiviral immunity in marine shrimp: inducible host mechanisms and evidence for the evolution of viral counter-responses.

Double-stranded RNA (dsRNA) is a common virus-associated molecular pattern and a potent inducer of antiviral responses in many organisms. While it is clear that the specific RNA interference (RNAi) response, a phenomenon triggered by dsRNA, serves antiviral functions in invertebrates, innate (non-specific) antiviral immune reactions induced by dsRNA (e.g. the Interferon response) have long been thought to be restricted to vertebrates. Recent work in an underappreciated experimental model, the penaeid shrimp, is challenging these traditional distinctions, by demonstrating the existence of both innate (non sequence-specific) and RNAi-related (sequence-specific) antiviral phenomena in crustacea. Here we discuss the evidence for this bivalent role of dsRNA in the initiation of antiviral responses in shrimp, and present new data that suggest that the antiviral functions of the shrimp RNAi machinery have imposed selective pressures on an evolving viral pathogen. These findings open the door for the discovery of novel mechanisms of innate immunity, and provide a basis for the future development of strategies to control viral diseases in the commercially important penaeid shrimp.

Animals↗
PubMed2003

The solitary wave of asexual evolution.

Using a previously undescribed approach, we develop an analytic model that predicts whether an asexual population accumulates advantageous or deleterious mutations over time and the rate at which either process occurs. The model considers a large number of linked identical loci, or nucleotide sites; assumes that the selection coefficient per site is much less than the mutation rate per genome; and includes back and compensating mutations. Using analysis and Monte Carlo simulations, we demonstrate the accuracy of our results over almost the entire range of population sizes. Two limiting cases of our results, when either deleterious or advantageous mutations can be neglected, correspond to the Fisher-Muller effect and Muller's ratchet, respectively. By comparing predictions of our model (no recombination) to those of simple single-locus models (strong recombination), we show that the accumulation of advantageous mutations is slowed by linkage over a broad, finite range of population size. This supports the view of Fisher and Muller, who argued in the 1930s that progressive evolution of organisms is slowed because loci at which beneficial mutations can occur are often linked together on the same chromosome. These results follow from our main finding, that distribution of sequences over the mutation number evolves as a traveling wave whose speed and width depend on population size and other parameters. The model explains a logarithmic dependence of steady-state fitness on the population size reported recently for an RNA virus.

Biological Evolution↗
PubMed1994

Protein-protein interactions and glycerophospholipids in bromovirus and nodavirus RNA replication.

The plant bromoviruses and animal nodaviruses are distinct groups of positive strand RNA viruses that have proven to be useful models for RNA replication studies. Bromoviruses encode two large proteins required for RNA replication: 1a contains domains implicated in helicase and capping functions, and 2a contains a central polymerase-like domain. Using immunoprecipitation and far-western blotting, we have now shown that 1a and 2a form a specific complex in vitro and have mapped the interacting domains. Molecular genetic data implicate the 1a-2a complex in RNA replication and suggest that it supports coordinate action of the putative helicase, polymerase, and capping domains. The locations of the interacting 1a and 2a domains have implications for replication models and the evolution of virus genomes bearing homologous replication genes in fused vs. divided forms. For the nodavirus Flock house virus (FHV), a true RNA replicase has been isolated that carries out complete, highly active replication of added FHV RNA, producing newly synthesized positive strand RNA in predominantly ssRNA form. Positive strand RNA synthesis in this FHV cell-free system is strongly dependent on the addition of any of several glycerophospholipids. Positive strand RNA synthesis depends on the complete glycerophospholipid structure, including the polar head group and diacyl glycerol lipid portion, and is strongly influenced by acyl chain length.

Bromovirus↗
PubMed1998

Arenavirus phylogeny: a new insight.

Arenaviridae is a worldwide distributed family, of enveloped, single stranded, RNA viruses. The arenaviruses were divided in two major groups (Old World and New World), based on serological properties and genetic data, as well as the geographic distribution. In this study the phylogenetic relationship among the members of the Arenaviridae was examined, using the reported genomic sequences. The comparison of the aligned nucleotide sequences of the S RNA and the predicted amino acid sequences of the GPC and N proteins, together with the phylogenetic analysis, strongly suggest a possible kinship of Pichindé and Oliveros viruses, with the Old World arenavirus group. This analysis points at the evolutive relationships between the arenaviruses of the Americas and can be used to evaluate the different hypotheses about their origin.

Arenavirus↗
PubMed1999

Viral RNA and evolved mutational robustness.

Many properties of organisms show great robustness against mutations. Whether this robustness is an evolved property or intrinsic to genetic systems is by and large unknown. An evolutionary origin of robustness would require a rethinking of key concepts in the field of molecular evolution, such as gene-specific neutral mutation rates, or the context-independence of deleterious mutations. We provide evidence that mutational robustness of the genome of RNA viruses to mutational changes in secondary structure has evolved. J. Exp. Zool. ( Mol. Dev. Evol.) 285:119-127, 1999.

Animals↗