The evolution of RNA viruses.
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Biological Evolution↗
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Treatment response and drug resistance in patients infected with HIV type 1 group O viruses.
Information about the efficacy of antiretroviral drugs in HIV-1 group O strains as well on the virus evolution in terms of resistance development in vivo is very limited. We assessed the clinical, immunological, and virological response to antiretroviral therapy as well as the selection of drug resistance in six HIV-1 group O-infected patients. All but one initiated antiretroviral therapy with two nucleoside reverse transcriptase inhibitors (NRTI) plus one protease inhibitor (PI). At baseline, median plasma HIV-1 group O RNA and CD4 counts were 32,256 (15,770-74,132) copies/ml and 88 cells/microl (13-170), respectively. Four patients reached undetectable plasma viremia 12 weeks after beginning treatment. However, viremia rebounded in one of them due to poor compliance. Another two patients had an initial reduction in plasma HIV-RNA greater than 1 log, but rebounded soon thereafter. At baseline, all patients' viruses revealed changes associated with NNRTI resistance (98G and 181C). Two out of three patients failing therapy developed resistance mutations. One selected changes M41L, E44D, D67N, V75M, M184V, and T215Y at the RT, and G48M, F53L, I54V, V82A, and L90M at the protease. Another selected mutations K70N, V75A, and M184V at the RT, and D30D/N and I84V at the protease while failing on indinavir. Interestingly, both patients showed a shift at codon 181 from C to Y, which might restore NNRTI susceptibility. Sustained viral suppression in HIV-1 group O-infected patients can be successfully achieved using antiretroviral regimens based on two NRTI and a boosted PI. Drug resistance mutations in HIV-1 group O seem to be selected at similar positions to those in HIV-1 group M viruses.
Adolescent↗
Surveillance activity for canine parvovirus in Italy.
Recent identification of unusual canine parvovirus (CPV) mutants in cats and dogs suggests that CPV type 2 (CPV-2), which emerged suddenly in the late 1970s, is undergoing continual genetic and antigenic variations. A peculiarity of parvoviruses is that single-nucleotide substitutions may determine drastic phenotypic changes. The effects of either natural or artificial mutations on CPV phenotypic properties have been largely investigated, and this sets up CPV as an interesting model to study virus evolution. By monitoring the evolution of CPV-2 in Italy, we observed the onset and quick spread of a Glu-426 mutant, antigenically different from the pre-existing variants that were partially displaced within a few years of the initial identification of the new mutant. The identification of CPV-2 variants raises several questions concerning their impact on the efficacy of the current CPV-2 vaccines, based on the original CPV-2 strain that no longer exists in the field.
Animals↗
JC virus regulatory region rearrangements and genotypes in progressive multifocal leukoencephalopathy: two independent aspects of virus variation.
JC virus (JCV) causes the central demyelinating disease progressive multifocal leukoencephalopathy (PML). JCV strains excreted in the urine are distinguishable from those in PML tissue by the configuration of their regulatory region to the right of ori: the archetypal regulatory region, 267 nucleotides long, is rearranged in PML tissue by deletion and duplication. Within the coding region JCV shows variations as a result of virus evolution. Four major genotypes are distinguishable of which Type 1 is based in Europe and Type 2 in Asia. Here, the regulatory region rearrangements and the viral genotypes of 29 JCV strains from PML brain were determined. Rearrangement patterns and genotypes were not associated. In general, deletions occurred before duplications, but exceptions to this rule exist. Each configuration of the 29 rearranged regulatory regions was unique and could be derived directly from the non-rearranged, archetypal form.
Gene Rearrangement↗
Continuing coevolution of virus and defective interfering particles and of viral genome sequences during undiluted passages: virus mutants exhibiting nearly complete resistance to formerly dominant defective interfering particles.
We quantitatively analyzed the interference interactions between defective interfering (DI) particles and mutants of cloned vesicular stomatitis virus passaged undiluted hundreds of times in BHK-21 cells. DI particles which predominated at different times in these serial passages always interfered most strongly (and very efficiently) with virus isolated a number of passages before the isolation of the DI particles. Virus isolated at the same passage level as the predominant DI particles usually exhibited severalfold resistance to these DI particles. Virus mutants (Sdi- mutants) isolated during subsequent passages always showed increasing resistance to these DI particles, followed by decreasing resistance as new DI particles arose to predominate and exert their own selective pressures on the virus mutant population. It appears that such coevolution of virus and DI particle populations proceeds indefinitely through multiple cycles of selection of virus mutants resistant to a certain DI particle (or DI particle class), followed by mutants resistant to a newly predominant DI particle, etc. At the peak of resistance, virus mutants were isolated which were essentially completely resistant to a particular DI particle; i.e., they were several hundred thousand-fold resistant, and they formed plaques of normal size and numbers in the presence of extremely high multiplicities of the DI particle. However, they were sensitive to interference by other DI particles. Recurring population interactions of this kind can promote rapid virus evolution. Complete sequencing of the N (nucleocapsid) and NS (polymerase associated) genes of numerous Sdi- mutants collected at passage intervals showed very few changes in the NS protein, but the N gene gradually accumulated a series of stable nucleotide and amino acid substitutions, some of which correlated with extensive changes in the Sdi- phenotype. Likewise, the 5' termini (and their complementary plus-strand 3' termini) continued to accumulate extensive base substitutions which were strikingly confined to the first 47 nucleotides. We also observed addition and deletion mutations in noncoding regions of the viral genome at a level suggesting that they probably occur at a high frequency throughout the genome, but usually with lethal or debilitating consequences when they occur in coding regions.
Amino Acid Sequence↗
Rapid reversion of sequence polymorphisms dominates early human immunodeficiency virus type 1 evolution.
The error-prone replication of human immunodeficiency virus type 1 (HIV-1) enables it to continuously evade host CD8+ T-cell responses. The observed transmission, and potential accumulation, of CD8+ T-cell escape mutations in the population may suggest a gradual adaptation of HIV-1 to immune pressures. Recent reports, however, have highlighted the propensity of some escape mutations to revert upon transmission to a new host in order to restore efficient replication capacity. To more specifically address the role of reversions in early HIV-1 evolution, we examined sequence polymorphisms arising across the HIV-1 genome in seven subjects followed longitudinally 1 year from primary infection. As expected, numerous nonsynonymous mutations were associated with described CD8+ T-cell epitopes, supporting a prominent role for cellular immune responses in driving early HIV-1 evolution. Strikingly, however, a substantial proportion of substitutions (42%) reverted toward the clade B consensus sequence, with nearly one-quarter of them located within defined CD8 epitopes not restricted by the contemporary host's HLA. More importantly, these reversions arose significantly faster than forward mutations, with the most rapidly reverting mutations preferentially arising within structurally conserved residues. These data suggest that many transmitted mutations likely incur a fitness cost that is recovered through retrieval of an optimal, or ancestral, form of the virus. The propensity of mutations to revert may limit the accumulation of immune pressure-driven mutations in the population, thus preserving critical CD8+ T-cell epitopes as vaccine targets, and argue against an unremitting adaptation of HIV-1 to host immune pressures.
CD8-Positive T-Lymphocytes↗
CD4+ immune escape and subsequent T-cell failure following chimpanzee immunization against hepatitis C virus.
Hepatitis C is a major cause of chronic liver disease, with 170 million individuals infected worldwide and no available vaccine. We analyzed the effects of an induced T-cell response in 3 chimpanzees, targeting nonstructural proteins in the absence of neutralizing antibodies. In all animals the specific T-cell response modified the outcome of infection, producing a 10- to 1,000-fold reduction in peak virus titers. The challenge of 2 immunized animals that had been previously exposed to hepatitis C virus resulted in subclinical infections. Immune responses in the third animal, naive prior to immunization, limited viral replication immediately, evidenced by a 30-fold reduction in virus titer by week 2, declining to a nonquantifiable level by week 6. After 10 weeks of immunological control, we observed a resurgence of virus, followed by progression to a persistent infection. Comparing virus evolution with T-cell recognition, we demonstrated that: (i) resurgence was concomitant with the emergence of new dominant viral populations bearing single amino acid changes in the NS3 and NS5A regions, (ii) these mutations resulted in a loss of CD4+ T-cell recognition, and (iii) subsequent to viral resurgence and immune escape a large fraction of NS3-specific T cells became impaired in their ability to secrete IFN-gamma and proliferate. In contrast, NS3-specific responses were sustained in the recovered/immunized animals presenting with subclinical infections. In conclusion, viral escape from CD4+ T cells can result in the eventual failure of an induced T-cell response that initially controls infection. Vaccines that can induce strong T-cell responses prior to challenge will not necessarily prevent persistent HCV infection.
Animals↗
[Evolution of plant viruses].
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Biological Evolution↗
Use of denaturing gradient gel electrophoresis for human polyomavirus JC sequence analysis.
Five genotypes of human polyomavirus JC (JCV) have been detected so far by nucleotide sequencing and by restriction fragment length polymorphism analysis. These genotypes are the result of geographically based virus evolution. However, interesting aspects of genotyping could involve both pathogenetic and diagnostic aspects. The product from amplification of JCV sequences, found in urine from 12 healthy individuals from different countries, have been analysed by denaturing gradient gel electrophoresis (DGGE) and by nucleotide sequencing. The aim of this study was to assess if the DGGE analysis could be used to study the variability of the JCV genome. The target sequence of this study was 233 bp long, within the gene coding for the VP1, known to contain several type-determining sites. Four DGGE patterns have been observed among our strains. Five strains, from African individuals, were of type 3 and exhibited the same electrophoretic pattern, clearly distinguishable from that of the type 1 strains detected in the urine from 6 European individuals. Five type 1 strains shared a similar DGGE pattern, slightly different from that of the sixth. A different pattern characterised as a type 2 strain was detected in the urine from a Peruvian individual. These results suggest that DGGE analysis could be used as a screening assay for choosing strains for nucleotide sequencing. The analysis of a fragment larger than the one used in this study could allow the identification of more types and subtypes.
Adolescent↗
The R203M and D377Y mutations of the nucleocapsid protein promote SARS-CoV-2 infectivity by impairing RIG-I-mediated antiviral signaling.
The viral protein mutations can modify virus-host interactions during virus evolution, and thus alter the extent of infection or pathogenicity. Studies indicate that nucleocapsid (N) protein of SARS-CoV-2 participates in viral genome assembly, intracellular signal regulation and immune interference. However, its biological function in viral evolution is not well understood. SARS-CoV-2 N protein mutations were analyzed in Delta, Omicron, and original strains. Two mutations with a methionine (M) residue at site 203 and a tyrosine (Y) residue at site 377 of the N protein were found in Delta strain but not in Omicron and original strains, and promoted SARS-CoV-2 infection therein. Those mutations, R203M and D377Y, enhanced the inhibitory impact of N protein on the impairment of RIG-I-mediated antiviral signaling, such as IRF3 phosphorylation and IFN-β activation. The viral RNA-binding activity of N protein was promoted by these mutations, effectively attenuating the recognition and interaction of RIG-I with viral RNA compared to the original or other variants. The R203M/D377Y mutations thus enhanced the suppressive activity of the N protein on RIG-I-mediated interferon induction both in vitro and in vivo, which in turn promoted viral replication. This study helps to understand the variability of SARS-CoV-2 in regulating host immunity.
SARS-CoV-2↗
JC virusType 2: definition of subtypes based on DNA sequence analysis of ten complete genomes.
Five major genotypes of JC virus (JCV) have been defined based on nucleotide differences in the VP1 gene of the DNA sequence. These types are probably a result of virus evolution in geographically isolated population groups. One of the first genotypes identified, Type 2, was found to represent strains of Asian origin. In order to further define the spectrum within Type 2 strains, the entire 5.1 kb genome of nine urinary strains of JCV was amplified by PCR with one pair of primers. These urine samples were obtained in the USA (California and New Mexico) from three European Americans, three Native Americans, two African Americans and one Hispanic American. The complete genome of an Asian JCV strain (Tokyo-1) isolated from progressive multifocal leukoencephalopathy (PML) brain in Japan was also sequenced. Here, we report the analysis of these ten DNA sequences and their deduced protein translations. Two phylogenetically distinct subtypes of Type 2 were found, 2A and 2B, which differ from each other by 0.8-1.1% of the coding region sequence. A 215 bp product amplified with primers in the VP1 gene contains enough sequence information to distinguish the major types and subtypes of JCV and is suitable for application in viral epidemiological studies. The investigation of these genomic variations is of special interest because JCV Type 2 strains are found at a significantly higher frequency in brain tissue of patients with PML than would be predicted from their excretion in a control population.
Adult↗
Complexities in ETS-domain transcription factor function and regulation: lessons from the TCF (ternary complex factor) subfamily. The Colworth Medal Lecture.
The ETS-domain transcription factor family can be divided into a series of subfamilies. Elk-1 represents the founding member of the ternary complex factor (TCF) subfamily. By focusing on the TCF subfamily, we can demonstrate the complexities that exist in the function and regulation of ETS-domain transcription factors. This article focuses on Elk-1 in detail and summarizes the functions of other TCFs. The key themes covered include the domain structure of the TCFs, the mechanisms of complex formation with serum response factor, regulation of TCFs by mitogen-activated protein kinase cascades, and transcriptional regulatory properties of the TCFs. Finally, the emerging role of the TCFs in vivo is discussed. A picture is developing indicating that, while these proteins exhibit significant sequence and functional conservation, key differences in their structure and regulation are being identified which may relate to unique functions of these proteins in vivo.
Amino Acid Sequence↗
Mathematical models of HIV pathogenesis and treatment.
We review mathematical models of HIV dynamics, disease progression, and therapy. We start by introducing a basic model of virus infection and demonstrate how it was used to study HIV dynamics and to measure crucial parameters that lead to a new understanding of the disease process. We discuss the diversity threshold model as an example of the general principle that virus evolution can drive disease progression and the destruction of the immune system. Finally, we show how mathematical models can be used to understand correlates of long-term immunological control of HIV, and to design therapy regimes that convert a progressing patient into a state of long-term non-progression.
Algorithms↗
Molecular detection and identification of an enterovirus during an outbreak of aseptic meningitis.
Stool samples from sixteen cases of children with meningitis originating from four different and geographically isolated parts of Greece were investigated for enteroviruses. The conventional method of cell culture in four different cell lines was initially used for the isolation of enteroviruses. The results showed a cytopathic effect (CPE) in all cases after two, or even more successive passages in only one cell line (RD), although a less-than-satisfactory CPE was obtained in many cases. Seroneutralization with RIVM mixed hyperimmune antisera followed and the isolates were typed as Coxsackie B viruses. The method of RT-PCR with enterovirus-specific primers targeted to the highly conserved 5'-UTR of the genome was initially used for the detection of enteroviruses from the inoculated cell cultures. A positive RT-PCR result was obtained for all of the clinical samples rapidly and accurately and the isolates were further characterized with the aid of Restriction Fragment Length Polymorphism (RFLP) analysis and Single Strand Conformation Polymorphism analysis (SSCP) of the amplicons. The RFLP analysis showed first of all that the isolates had an identical restriction pattern with Coxsackie B5 Faulkner reference strain with 4 out of 5 restriction enzymes and secondly, both RFLP and SSCP analysis indicated the epidemiological association of the isolates. The speed of the molecular methodology that was used in comparison with the conventional methods and its possible significance for the description of virus evolution and circulation in the populations is discussed.
Animals↗
Dendritic cell susceptibility to hepatitis C virus genotype 1 infection.
In vitro infection of human monocyte-derived dendritic cells was carried out to study their susceptibility to hepatitis C virus (HCV) infection. Immature dendritic cells and mature dendritic cells were incubated overnight at 37 degrees C with HCV-positive (genotype 1) serum samples; the presence of the viral genome associated with the production of its replicative intermediate was used as evidence of infection. In immature dendritic cells, HCV RNA was detectable from days 1-10 post-infection (p.i.), and de novo synthesis of negative-strand HCV RNA could be demonstrated by a strand-specific rTth reverse transcription-polymerase chain reaction at day 2. In mature dendritic cells, the positive-strand form was detectable from days 1-5 p.i., while the negative-strand HCV RNA appeared at days 1 and 2 p.i. Quasispecies present in the inoculum and 6 days p.i. were analyzed by sequencing hypervariable region 1 of the E2 protein. Only two of seven HVR variants present in the inoculum were found in HCV-infected immature dendritic cells. Another two HVR variants not found in the inoculum were recovered from infected immature dendritic cells, suggesting serum minor variants selection or virus evolution during in vitro replication. Analysis by single-strand conformation polymorphism assay of 5' untranslated region of HCV sequences showed that the patterns obtained from the inoculum and infected immature dendritic cells and mature dendritic cells differed slightly. These findings indicate that both immature dendritic cells and mature dendritic cells are susceptible to HCV genotype 1 infection, supporting at least HCV RNA replication. This model should be a valuable tool for the study of modulation of dendritic cell functions in HCV infection.
Amino Acid Sequence↗
Conformational flexibility in a highly mobile protein loop of foot-and-mouth disease virus: distinct structural requirements for integrin and antibody binding.
The G-H loop of foot-and-mouth disease virus VP1 protein is a highly mobile peptide, that extends from the capsid surface and that in native virions is invisible by X-ray crystallography. In serotype C, this segment contains a hypervariable region with several continuous, overlapping, B-cell epitopes that embrace the conserved Arg-Gly-Asp (RGD) cell attachment motif. The solvent-exposed positioning of this peptide by selective insertion into different structural frameworks of E. coli beta-galactosidase, generates a spectrum of antigenic variants which react distinctively with a panel of anti-VP1 monoclonal antibodies and exhibit different efficiencies as cell ligands. The cell attachment efficiency is much less restricted by the different positioning of the viral segment at the insertion sites. A molecular model of an inserted stretch reveals a highest flexibility of the RGD tripeptide segment compared with the flanking sequences, that could allow a proper accommodation to integrin receptors even in poorly antigenic conformations. The non-converging structural requirements for RGD-mediated integrin binding and antibody recognition, explains the dynamism of the generation of neutralisation-resistant antigenic variants in the viral quasi-species, arising from a conformational space of integrin-binding competent peptides. This might be of special relevance for foot-and-moth disease virus evolution, since unlike in other picornaviruses, the cell binding motif and the major neutralising B-cell epitopes overlap in a solvent-exposed peptide accessible to the host immune system, in a virion lacking canyons and similar hiding structures.
Amino Acid Sequence↗
Functional consequences of mutations in HIV-1 Gag p55 selected by CTL pressure.
Amino acid changes in the CA domain of the p55 Gag protein of HIV-1 have been observed during the course of an infection that appear to correlate with escape from cytotoxic T cell surveillance (Phillips et al., Nature 354, 453-459, 1991). A corollary of this observation is that all such changes should be functionally silent but, as the changes were observed in populations of virus, this has not been formally demonstrated. We have introduced the amino acid changes representative of those observed to occur in vivo into the Gag p55 gene cloned in the baculovirus expression system where the wild-type gene product produces virus-like particles (VLP). We show that none of these mutations affect particle formation as judged by VLP morphology and density despite their location within a sequence of the Gag open reading frame known to be important for assembly. These data add tacit support to the hypothesis that CTL pressure can drive virus evolution in HIV and add to the fine mapping of sequences involved in Gag subunit interactions.
Amino Acid Sequence↗
The Env-like open reading frame of the baculovirus-integrated retrotransposon TED encodes a retrovirus-like envelope protein.
TED is a 7.5-kbp member of the gypsy family of retrotransposons that was first identified by its integration within the baculovirus DNA genome. This lepidopteran (moth) transposon contains three retrovirus-like genes, including functional gag and pol that yield reverse transcriptase-containing virus-like particles. To identify and characterize the product(s) of the third env-like open reading frame, TED ORF3 was expressed in homologous lepidopteran cells by using a baculovirus vector, vENV. Immunoblots and immunoprecipitations with antiserum raised against a bacterial ORF3-fusion protein detected two ORF3-encoded proteins, p68env and gp75env. On the basis of selective incorporation of [3H]mannose and inhibition of modification by tunicamycin which blocks N-linked glycosylation, gp75env is a glycoprotein derived from core precursor p68env. As predicted by the presence of a transmembrane domain near the carboxyl terminus, both p68env and gp75env were associated with heavy membranes of vENV-infected cells. Thus, TED ORF3 encodes a membrane glycoprotein with properties characteristic of retroviral env proteins. These data are consistent with the hypothesis that TED is an invertebrate retrovirus. Moreover, TED integration within the baculovirus genome provides an example of retroelement-mediated acquisition of host genes that may contribute to virus evolution.
Animals↗