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PubMedDate not supplied

Evolution of hepatitis C virus-specific T cell responses and cytokine production in chronic hepatitis C patients treated with high doses of interferon-alpha.

OBJECTIVE: To assess the evolution of in vitro T cell response to hepatitis C virus (HCV) Core, E1, E2 and NS3 antigens in 10 patients with chronic hepatitis C, before, during and after a high dose interferon alpha (IFN-alpha) therapy, and to evaluate the influence of IFN-alpha on the in vivo and in vitro production of tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma). METHODS: T cell response to HCV antigens was evaluated by lymphoproliferation assays. In vivo and in vitro cytokine production was evaluated at weeks 0, 4, 8, and 12 of IFN-alpha therapy by enzyme immunoassays. RESULTS: In general, of all HCV antigens tested throughout the follow-up, those belonging to the Core region were the most immunostiumlatory. This observation was valid in IFN-alpha responders as well as IFN-alpha non-responders. The lymphoproliferative response to HCV antigens increased during IFN-alpha therapy. Serum levels of TNF-alpha were significantly increased in HCV patients, and six out of ten patients showed increased IFN-gamma serum levels. A significant decrease of IFN-gamma levels was observed during therapy and the same trend was seen for TNF-alpha. Mitogen-stimulated TNF-alpha and IFN-gamma production before therapy did not differ from that of normal controls, however, the cytokine production was reduced at week 4 of therapy, corresponding with a clinical improvement. A return to pretreatment values was observed after 8 weeks of therapy. CONCLUSIONS: a) Core antigens are the most immunostimulatory HCV antigens at the T cell level in chronic hepatitis C patients; b) High dose IFN-alpha therapy induces an increase in lymphoproliferative response to HCV antigens; c) Serum levels of TNF-alpha are increased in HCV patients; d) High dose IFN-alpha therapy induces a decrease in serum levels of IFN-gamma; e) High dose IFN-alpha therapy induces a transiently decreased mitogen-induced TNF-alpha and IFN-gamma production.

Adult↗
PubMed1996

Genetic characterization of two phenotypically distinct North American ovine lentiviruses and their possible origin from caprine arthritis-encephalitis virus.

Ovine and caprine lentiviruses are closely related genetically and antigenically although the diseases that these viruses cause in their respective host animals can vary greatly. In sheep, syndromes consist primarily of interstitial pneumonia with rare occurrences of arthritis and encephalitis, whereas in goats, the disease expresses mainly as arthritis in adult animals with rare cases of encephalitis in newborns. Experimentally, viruses from either sheep or goats can infect animals of the reciprocal species and many field strains of ovine lentivirus have biological properties similar to those of caprine viruses. However, a molecular correlation for the phenotypic differences between ovine and caprine lentivirus strains is unknown. To investigate this, we examined genetic characteristics of two phenotypically distinct North American ovine lentiviruses. Nucleotide sequence analysis of the envelope regions from virus strains 85/34 and 84/28 showed that despite significant biological differences, these viruses are closely related to each other and are genotypically more homologous to caprine arthritis-encephalitis virus (CAEV) than to visna virus of sheep. Furthermore, analysis of the nucleotide substitutions in their env regions indicated that when differences between the two ovine viruses and CAEV were found, the changes often resulted in nucleotides homologous with visna virus. These results suggest that the two field strains of ovine lentivirus may have originated from a cross-species infection of sheep by a CAEV-like virus and, evolution of their genomes toward that of ovine lentivirus may be reflective of adaptation of these viruses to the new ovine host.

Animals↗
PubMed2001

The familiar and the unexpected in structures of icosahedral viruses.

Viruses were the first large macromolecular assemblages to be visualized at high resolution. New virus structures continue to challenge our understanding of specificity in protein-protein "recognition". The evolution of virus structures has been even more opportunistic than previously imagined.

Biological Evolution↗
PubMed2001

Substitution model of sequence evolution for the human immunodeficiency virus type 1 subtype B gp120 gene over the C2-V5 region.

Phylogenetic analyses frequently rely on models of sequence evolution that detail nucleotide substitution rates, nucleotide frequencies, and site-to-site rate heterogeneity. These models can influence hypothesis testing and can affect the accuracy of phylogenetic inferences. Maximum likelihood methods of simultaneously constructing phylogenetic tree topologies and estimating model parameters are computationally intensive, and are not feasible for sample sizes of 25 or greater using personal computers. Techniques that initially construct a tree topology and then use this non-maximized topology to estimate ML substitution rates, however, can quickly arrive at a model of sequence evolution. The accuracy of this two-step estimation technique was tested using simulated data sets with known model parameters. The results showed that for a star-like topology, as is often seen in human immunodeficiency virus type 1 (HIV-1) subtype B sequences, a random starting topology could produce nucleotide substitution rates that were not statistically different than the true rates. Samples were isolated from 100 HIV-1 subtype B infected individuals from the United States and a 620 nt region of the env gene was sequenced for each sample. The sequence data were used to obtain a substitution model of sequence evolution specific for HIV-1 subtype B env by estimating nucleotide substitution rates and the site-to-site heterogeneity in 100 individuals from the United States. The method of estimating the model should provide users of large data sets with a way to quickly compute a model of sequence evolution, while the nucleotide substitution model we identified should prove useful in the phylogenetic analysis of HIV-1 subtype B env sequences.

Evolution, Molecular↗
PubMed2005

Clade replacements in dengue virus serotypes 1 and 3 are associated with changing serotype prevalence.

The evolution of dengue virus (DENV) is characterized by phylogenetic trees that have a strong temporal structure punctuated by dramatic changes in clade frequency. To determine the cause of these large-scale phylogenetic patterns, we examined the evolutionary history of DENV serotype 1 (DENV-1) and DENV-3 in Thailand, where gene sequence and epidemiological data are relatively abundant over a 30-year period. We found evidence for the turnover of viral clades in both serotypes, most notably in DENV-1, where a major clade replacement event took place in genotype I during the mid-1990s. Further, when this clade replacement event was placed in the context of changes in serotype prevalence in Thailand, a striking pattern emerged; an increase in DENV-1 clade diversity was associated with an increase in the abundance of this serotype and a concomitant decrease in DENV-4 prevalence, while clade replacement was associated with a decline in DENV-1 prevalence and a rise of DENV-4. We postulate that intraserotypic genetic diversification proceeds at times of relative serotype abundance and that replacement events can result from differential susceptibility to cross-reactive immune responses.

Dengue↗
PubMed2005

Genome-wide screen identifies host genes affecting viral RNA recombination.

Rapid evolution of RNA viruses with mRNA-sense genomes is a major concern to health and economic welfare because of the devastating diseases these viruses inflict on humans, animals, and plants. To test whether host genes can affect the evolution of RNA viruses, we used a Saccharomyces cerevisiae single-gene deletion library, which includes approximately 80% of yeast genes, in RNA recombination studies based on a small viral replicon RNA derived from tomato bushy stunt virus. The genome-wide screen led to the identification of five host genes whose absence resulted in the rapid generation of new viral RNA recombinants. Thus, these genes normally suppress viral RNA recombination, but in their absence, hosts become viral recombination "hotbeds." Four of the five suppressor genes are likely involved in RNA degradation, suggesting that RNA degradation could play a role in viral RNA recombination. In contrast, deletion of four other host genes inhibited virus recombination, indicating that these genes normally accelerate the RNA recombination process. A comparison of deletion strains with the lowest and the highest recombination rate revealed that host genes could affect recombinant accumulation by up to 80-fold. Overall, our results demonstrate that a set of host genes have a major effect on RNA virus recombination and evolution.

DNA Primers↗
PubMed1989

Characterization of vaccinia virus deletion mutants isolated from persistently infected Friend erythroleukemia cells.

Persistent viral infections in vitro are useful to study the evolution of virus populations in the absence of immunological pressure. Several deletion mutants have been isolated in this laboratory from Friend erythroleukemia cells persistently infected with vaccinia virus strain IHD-W, designated SQAvac. Two of the mutants, which remain stable after serial passage in L cells, have been characterized. The deletion which range between 20 to 22 kb, has been localized at the left terminus comprising HindIII fragments C and N. In addition, HindIII B fragment lost the sequences that hybridize to pAG5, a plasmid containing the 3.5 kb terminal sequences and acquired different restriction sites. Phenotypic characterization of these mutants revealed that they were not replication defective since they grew in all cell lines tested and produced plaques of the same size as the wild-type. However, they were less effective in suppressing host protein synthesis. The LD50 for the mutants titered in NIH Swiss female mice was greater than 10(9) PFU as compared to 10(6) PFU for the wild-type, indicating reduced virulence in vivo. These mutants, which display different properties to previously described mutants with deletions at the left terminus, provide another valuable system to study the molecular basis of virulence of vaccinia.

Animals↗
PubMed2006

Dynamics of mutation and recombination in a replicating population of complementing, defective viral genomes.

In a previous study, we documented that serial passage of a biological clone of foot-and-mouth disease virus (FMDV) at high multiplicity of infection (moi) in cell culture resulted in viral populations dominated by defective genomes that included internal in-frame deletions, affecting the L and capsid-coding regions, and were infectious by complementation. In the present study, analyses of the defective genomes present in individual viral plaques, and of consensus nucleotide sequences determined for the entire genomes of sequential samples, have revealed a continuous dynamics of mutation and recombination. At some points of high genetic instability, multiple minority genomes with different internal deletions co-existed in the population. At later passages, a new defective RNA arose and displaced a related, previously dominant RNA. Nucleotide sequences of the different genomic forms found in sequential isolates have revealed an accumulation of mutations at an average rate of 0.12 substitutions per genome per passage. At the regions around the deletion sites, substantial, minor or no nucleotide sequence identity is found, suggesting relaxed sequence requirements for the occurrence of internal deletions. Competition experiments indicate a selective advantage of late phase defective genomes over their precursor forms. The defective genome-based FMDV retained an expansion of host cell tropism, undergone by the standard virus at a previous stage of the same evolutionary lineage. Thus, despite a complex dynamics of mutation and recombination, and phases of high genetic instability, a biologically relevant phenotypic trait was stably maintained after the evolutionary transition towards a primitive genome segmentation. The results extend the concept of a complex spectrum of mutant genomes to a complex spectrum of defective genomes in some evolutionary transitions of RNA viruses.

Animals↗
PubMed2004

Glycosyltransferases encoded by viruses.

Studies of cellular biology in recent decades have highlighted the crucial roles of glycans in numerous important biological processes, raising the concept of glycomics that is now considered as important as genomics, transcriptomics and proteomics. For millions of years, viruses have been co-evolving with their hosts. Consequently, during this co-evolution process, viruses have acquired mechanisms to mimic, hijack or sabotage host processes that favour their replication, including mechanisms to modify the glycome. The importance of the glycome in the regulation of host-virus interactions has recently led to a new concept called 'glycovirology'. One fascinating aspect of glycovirology is the study of how viruses affect the glycome. Viruses reach that goal either by regulating expression of host glycosyltransferases or by expressing their own glycosyltransferases. This review describes all virally encoded glycosyltransferases and discusses their established or putative functions. The description of these enzymes illustrates several intriguing aspects of virology and provides further support for the importance of glycomics in biological processes.

Bacteriophages↗
PubMed1998

[Serotypes and genotypes of dengue virus circulating in Venezuela, 1990-1997].

Due to the increasing severity of hemorrhagic dengue epidemics during the last years in Venezuela, a retrospective analysis was conducted to identify the behaviour of the dengue virus serotypes circulating in the country and the molecular evolution of dengue virus serotype 2. The data presented here indicates that dengue virus serotypes 1, 2 and 4 are endemic in Venezuela, they circulate simultaneously around the year in the biggest urban cities, however, one particular serotype is predominant during an epidemic period and replaces the virus serotype dominant during the previous epidemic period. The increased severity of dengue fever since 1989 in Venezuela might be associated to the introduction of the Asiatic genotype of virus which replaced the autochthonous Caribbean genotype. The Asiatic genotype is recognised as a more virulent virus.

Dengue↗
PubMed1991

Importance of purine and pyrimidine content of local nucleotide sequences (six bases long) for evolution of the human immunodeficiency virus type 1.

Human immunodeficiency virus type 1 evolves rapidly, and random base change is thought to act as a major factor in this evolution. However, segments of the viral genome differ in their variability: there is the highly variable env gene, particularly hypervariable regions located within env, and, in contrast, the conservative gag and pol genes. Computer analysis of the nucleotide sequences of human immunodeficiency virus type 1 isolates reveals that base substitution in this virus is nonrandom and affected by local nucleotide sequences. Certain local sequences 6 base pairs long are excessively frequent in the hypervariable regions. These sequences exhibit base-substitution hotspots at specific positions in their 6 bases. The hotspots tend to be nonsilent letters of codons in the hypervariable regions--thus leading to marked amino acid substitutions there. Conversely, in the conservative gag and pol genes the hotspots tend to be silent letters because of a difference in codon frame from the hypervariable regions. Furthermore, base substitutions in the local sequences that frequently appear in the conservative genes occurred at a low level, even within the variable env. Thus, despite the high variability of this virus, the conservative genes and their products could be conserved. These may be some of the strategies evolved in human immunodeficiency virus type 1 to allow for positive-selection pressures, such as the host immune system, and negative-selection pressures on the conservative gene products.

Acquired Immunodeficiency Syndrome↗
PubMed2003

Geminivirus disease complexes: an emerging threat.

Small circular single-stranded DNA satellites have recently been isolated from plants infected with whitefly-transmitted monopartite begomoviruses. The satellites, named DNA beta, depend on the helper viruses for their proliferation and, in turn, are required for helper virus accumulation and symptom expression. They are highly diverse yet retain an overall conserved structure with respect to potential coding regions and regulatory elements. The begomovirus-satellite disease complexes are associated with economically important diseases, and have been isolated from vegetable and fibre crops, ornamental plants and weeds throughout Africa and Asia. Their widespread distribution and diversity, coupled to the global movement of plant material and the dissemination of the whitefly vector, suggests that these disease complexes pose a serious threat to tropical and sub-tropical agro-ecosystems worldwide.

Africa↗
PubMed2001

Genetic 'budget' of viruses and the cost to the infected host: a theory on the relationship between the genetic capacity of viruses, immune evasion, persistence and disease.

The nature of the pathogen-host relationship is recognized as being a dynamic coevolutionary process where the immune system has required ongoing adaptation and improvement to combat infection. Under survival pressure from sophisticated immune responses, adaptive processes for microbes, including viruses, have manifested as immune evasion strategies. This paper proposes a theory that virus immune evasion can be broadly classified into 'acquisition' or 'erroneous replication' strategies. Acquisition strategies are characteristic of large genome dsDNA viruses, which (i) replicate in the cell nucleus; (ii) have acquired host genes that can be used to directly manipulate responses to infection; (iii) are often latent for the lifetime of the host; and (iv) have little or no serious impact on health. Alternatively, erroneous replication strategies are characteristic of small genome RNA viruses, which are recognized as being the cause of many serious diseases in humans. It is proposed that this propensity for disease is due to the cytoplasmic site of replication and truncated temporal relationship with the host, which has limited or removed the evolutionary opportunity for RNA viruses to have acquired host genes. This has resulted in RNA viruses relying on error-prone replication strategies which, while allowing survival and persistence, are more likely to lead to disease due to the lack of direct viral control over potentially host-deleterious inflammatory and immune responses to infection.

Animals↗
PubMed2006

Does cytomegalovirus play a causative role in the development of various inflammatory diseases and cancer?

Human cytomegalovirus (HCMV) is a herpes virus that infects and is carried by 70-100% of the world's population. During its evolution, this virus has developed mechanisms that allow it to survive in an immunocompetent host. For many years, HCMV was not considered to be a major human pathogen, as it appeared to cause only rare cases of HCMV inclusion disease in neonates. However, HCMV is poorly adapted for survival in the immunosuppressed host and has emerged as an important human pathogen in AIDS patients and in patients undergoing immunosuppressive therapy following organ or bone marrow transplantation. HCMV-mediated disease in such patients has highlighted the possible role of this virus in the development of other diseases, in particular inflammatory diseases such as vascular diseases, autoimmune diseases and, more recently, with certain forms of cancers. Current research is focused on determining whether HCMV plays a causative role in these diseases or is merely an epiphenomenon of inflammation. Inflammation plays a central role in the pathogenesis of HCMV. This virus has developed a number of mechanisms that enable it to hide from the cells of the immune system and, at the same time, reactivation of a latent infection requires immune activation. Numerous products of the HCMV genome are devoted to control central functions of the innate and adaptive immune responses. By influencing the regulation of various cellular processes including the cell cycle, apoptosis and migration as well as tumour invasiveness and angiogenesis, HCMV may participate in disease development. Thus, the various drugs now available for treatment of HCMV disease (e.g. ganciclovir, acyclovir and foscarnet), may also prove to be useful in the treatment of other, more widespread diseases.

Animals↗
PubMed1979

Evolution of human influenza A viruses in nature: sequential mutations in the genomes of new H1N1.

The genetic variation of the new pandemic H1N1 influenza A viruses isolated in 1977 was analyzed by two-dimensional oligonucleotide fingerprinting and RNA sequencing. Differences were observed in the fingerprints of the RNAs of these viruses, and analysis of the changes suggested that sequential mutations occurred in their genomes. Based on these data, a scheme is presented which proposes divergent evolution of strains from a common ancestry. Furthermore, it was found that mutations were not restricted to the genes coding for the hemagglutinin and the neuraminidase, but were scattered throughout the genome, suggesting that selective antibody pressure is not solely responsible for the emergence of genetic variants. Our data also strengthen the hypothesis that the new H1N1 influenza virus strains are derived from strains circulating in 1950.

Antigens, Viral↗
PubMed2006

Comparative studies on mucosal and intravenous transmission of simian immunodeficiency virus (SIVsm): the kinetics of evolution to neutralization resistance are related to progression rate of disease.

The kinetics of appearance of autologous neutralizing antibodies were studied in cynomolgus macaques infected with simian immunodeficiency virus (SIVsm) by the intravenous (IV) route (six monkeys) or the intrarectal (IR) route (ten monkeys). The SIVsm inoculum virus and reisolates obtained at 2 weeks, 3 or 4 months and later than 1 year were tested in a GHOST(3) cell line-based plaque-reduction assay with autologous sera collected at the same sampling times. All monkeys developed a neutralizing-antibody response to the inoculum virus, those infected by the IV route earlier than monkeys infected by the IR route. Animals were divided into progressor (P), slow-progressor (SP) and long-term non-progressor (LTNP) monkeys, based on progression rate. In P monkeys, neutralization escape could be demonstrated by 3 months post-infection. Neutralization-resistant variants also emerged in SP and LTNP monkeys, but were much delayed compared with P monkeys. Evolution of neutralization resistance was also demonstrated by a positive-control serum in the heterologous reaction. Pooled sera from four LTNP monkeys showed a broad neutralizing capacity, including neutralization of escape variants. These results from a large group of infected monkeys showed that SIV evolves to neutralization resistance in the infected host and that the kinetics of this evolution are related to the route of transmission and the progression rate of SIV disease. The results suggest an important role for neutralizing antibodies in controlling viraemia. Although this control is transient in the infected host, neutralization resistance is relative and variant viruses may be neutralized by a broadly cross-neutralizing serum pool.

Animals↗
PubMed2004

Novel predicted peptidases with a potential role in the ubiquitin signaling pathway.

A multi-pronged strategy including extensive sequence searches, structural modeling, and analysis of contextual information extracted from domain architectures, genetic screens, and large-scale protein-protein interaction analyses was employed to predict previously undetected components of the eukaryotic ubiquitin (Ub) signaling system. Two novel groups of proteins that are likely to function as de-ubiquitinating and de-SUMOylating peptidases (DUBs) were identified. The first group of putative DUBs, designated PPPDE superfamily (after Permuted Papain fold Peptidases of DsRNA viruses and Eukaryotes), consists of predicted thiol peptidases with a circularly permuted papain-like fold. The inference of the likely DUB function of the PPPDE superfamily proteins is based on the fusions of the catalytic domain to Ub-binding PUG (PUB)/UBA domains and a novel alpha-helical Ub-associated domain (the PUL domain, after PLAP, Ufd3p and Lub1p). The presence of the PPPDE superfamily proteins in most eukaryotic lineages, including basal ones, such as Giardia, suggests a role in deubiquitination of highly conserved proteins involved in key cellular functions, such as cell cycle control. In addition to eukaryotic proteins, the PPPDE superfamily includes predicted proteases from several groups of double-stranded RNA viruses and one single-stranded DNA virus. The apparent recruitment of DUBs for viral polyprotein processing seems to represent a common theme in evolution of viruses. The second group of putative DUBs identified in this study is the WLM (Wss1p-like metalloproteases) family of the Zincin-like superfamily of Zn-dependent peptidases, which are linked to the Ub-system by virtue of fusions with the UB-binding PUG (PUB), Ub-like, and Little Finger domains. More specifically, genetic evidence implicates the WLM family in de-SUMOylation. If validated experimentally, the WLM family proteins will represent the first case of a Zincin-like metalloprotease involvement in Ub-signaling.

Amino Acid Sequence↗