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At least 325 records · Page 18Linked to original sources

Rapid evolution of chronic viral hepatitis into hepatocellular carcinoma after beta-interferon treatment.

A 62-year-old man, affected by Chronic Active Hepatitis (discovered in 1993) and treated with interferon, referred to our department with increased abdominal volume, persistent abdominal pain, continuous-remittent fever and jaundice. CT scan of the liver revealed a hypodense, not capsulated, infiltrative, solid formation in the right lobe. US guided biopsy showed multinucleated giant cells, with eosinophilic cytoplasm and pleomorphism of the nuclei, arranged in several thick trabecula lined by endothelial cells or formed bile containing acini. In our case, the rapid evolution of chronic viral hepatitis towards HCC calls for a careful evaluation of the role of IFN therapy, since this drug is widely used in chronic liver diseases.

Antiviral Agents↗

Evolution of hepatitis B viral load and viral genome sequence during adefovir dipivoxil therapy.

Phase II and III clinical trials of adefovir dipivoxil (ADV) for the treatment of chronic hepatitis B have shown that this hepadnavirus polymerase inhibitor is well tolerated and effectively suppresses hepatitis B virus (HBV) replication. We therefore analysed the evolution of viral load and the emergence of HBV polymerase mutants in a 22-patient subgroup from a phase III clinical trial of ADV for the treatment of HBeAg-positive chronic hepatitis B. HBV DNA serum titres were quantified using a real-time polymerase chain reaction (PCR) assay with molecular hybridization probes. Emergence of polymerase mutants was assessed by direct sequencing of the viral reverse transcriptase domain after PCR amplification of HBV DNA isolated from serum. Our results indicated that ADV therapy effectively suppressed HBV replication in these patients (median serum HBV decrease at week 48 of treatment = 4.3 log10 copies/mL). The initial drop of HBV DNA titres in serum at week 12 of ADV therapy seemed to be predictive of subsequent HBe seroconversion (P = 0.059). Neither viral breakthrough nor the selection of drug resistant mutants were observed during the study period. Our results showed that ADV administration for 48-72 weeks effectively suppresses HBV replication without the emergence of resistant viral mutants.

Adenine↗

Scientific rationale for antiretroviral therapy in 2005: viral reservoirs and resistance evolution.

Hope for a cure for HIV-1 infection was dampened by the discovery of a latent form of the virus that persists in resting CD4+ cells. This reservoir of latently HIV-infected resting memory T cells represents an archive of viral genotypes produced in an individual from the onset of infection. Entry into the reservoir is stopped with suppressive antiretroviral therapy, but the archived viruses are capable of re-initiating active infections, are released continuously from this reservoir, and can cause viral rebound if antiretroviral therapy is stopped. Studies of residual low-level viremia (<50 HIV RNA copies/mL of plasma) in the setting of effective antiretroviral therapy indicate that such viremia is largely caused by activation of the latently infected cells and the release of virus from this and other stable reservoirs. These studies support the notion that the stability of the latent reservoir is consistent with the long life span of resting memory T cells, rather than reflecting rounds of active replication under suppressive antiretroviral therapy that replenish the reservoir. There may be other stable reservoirs in addition to the resting T-cells pool, further complicating the problem of eradication. This article summarizes a presentation on viral reservoirs and viral evolution by Robert F. Siliciano, MD, PhD, at the International AIDS Society-USA course in New York in March 2005.

Anti-HIV Agents↗

On the origin and evolution of vertebrate and viral profilins.

The three dimensional structures of profilins from invertebrates and vertebrates are remarkably similar despite low sequence similarity. Their evolutionary relationship remains thus enigmatic. A phylogenetic analysis of profilins from Deuterostoma indicates that profilin III and IV isoforms each form distinct groups. Profilin IV is most related to invertebrate profilins and originated prior to vertebrate evolution whereas separation of profilin I, II and III isoforms occurred early in vertebrate evolution. Viral profilins are most similar to profilin III. In silico analysis of representative profilin gene structures corroborates the phylogenetic result and we discuss this in terms of biochemical differences.

Animals↗

Viral diseases and human evolution.

The interaction of man with viral agents was possibly a key factor shaping human evolution, culture and civilization from its outset. Evidence of the effect of disease, since the early stages of human speciation, through pre-historical times to the present suggest that the types of viruses associated with man changed in time. As human populations progressed technologically, they grew in numbers and density. As a consequence different viruses found suitable conditions to thrive and establish long-lasting associations with man. Although not all viral agents cause disease and some may in fact be considered beneficial, the present situation of overpopulation, poverty and ecological inbalance may have devastating effects on human progress. Recently emerged diseases causing massive pandemics (e.g., HIV-1 and HCV, dengue, etc.) are becoming formidable challenges, which may have a direct impact on the fate of our species.

Biological Evolution↗

A cellular homolog of hepatitis delta antigen: implications for viral replication and evolution.

Hepatitis delta virus (HDV) is a pathogenic human virus whose RNA genome and replication cycle resemble those of plant viroids. However, viroid genomes contain no open reading frames, whereas HDV RNA encodes a single protein, hepatitis delta antigen (HDAg), which is required for viral replication. A cellular gene whose product interacts with HDAg has now been identified, and this interaction was found to affect viral genomic replication in intact cells. DNA sequence analysis revealed that this protein, termed delta-interacting protein A (DIPA), is a cellular homolog of HDAg. These observations demonstrate that a host gene product can modulate HDV replication and suggest that HDV may have evolved from a primitive viroidlike RNA through capture of a cellular transcript.

Adaptor Proteins, Signal Transducing↗

Using hidden Markov models and observed evolution to annotate viral genomes.

MOTIVATION: ssRNA (single stranded) viral genomes are generally constrained in length and utilize overlapping reading frames to maximally exploit the coding potential within the genome length restrictions. This overlapping coding phenomenon leads to complex evolutionary constraints operating on the genome. In regions which code for more than one protein, silent mutations in one reading frame generally have a protein coding effect in another. To maximize coding flexibility in all reading frames, overlapping regions are often compositionally biased towards amino acids which are 6-fold degenerate with respect to the 64 codon alphabet. Previous methodologies have used this fact in an ad hoc manner to look for overlapping genes by motif matching. In this paper differentiated nucleotide compositional patterns in overlapping regions are incorporated into a probabilistic hidden Markov model (HMM) framework which is used to annotate ssRNA viral genomes. This work focuses on single sequence annotation and applies an HMM framework to ssRNA viral annotation. A description of how the HMM is parameterized, whilst annotating within a missing data framework is given. A Phylogenetic HMM (Phylo-HMM) extension, as applied to 14 aligned HIV2 sequences is also presented. This evolutionary extension serves as an illustration of the potential of the Phylo-HMM framework for ssRNA viral genomic annotation. RESULTS: The single sequence annotation procedure (SSA) is applied to 14 different strains of the HIV2 virus. Further results on alternative ssRNA viral genomes are presented to illustrate more generally the performance of the method. The results of the SSA method are encouraging however there is still room for improvement, and since there is overwhelming evidence to indicate that comparative methods can improve coding sequence (CDS) annotation, the SSA method is extended to a Phylo-HMM to incorporate evolutionary information. The Phylo-HMM extension is applied to the same set of 14 HIV2 sequences which are pre-aligned. The performance improvement that results from including the evolutionary information in the analysis is illustrated.

Algorithms↗

Antigenic drift and variability of influenza viruses.

Annual influenza epidemics are caused by rapid evolution of the viral genome. Continuous and extensive antigenic variation has been shown for hemagglutinin (HA), the principal immunizing antigen of the virus. Monitoring of the antigenicity of circulating influenza viruses is necessary for selection of the most suitable vaccine strains. In this study, characterization of influenza A/H3N2 and influenza B viruses recently circulating in Germany was performed by molecular and antigenic analysis. Sequencing and phylogenetic analysis of the HA1 gene revealed that two distinct groups of H3N2 viruses co-circulated during 1997/1998. The majority of isolates clustered with the new drift variant A/Sydney/5/97, as was also shown by antigenic characterization. A noteworthy genetic drift of H3N2 viruses was evident during the winter 1998/1999. However, serological characterization using hemagglutinin inhibition tests did not result in detection of viruses belonging to different groups as confirmed by molecular analysis. Influenza B viruses isolated during 1996/1997 were antigenically closely related to the prototype vaccine strains B/Beijing/184/93 or B/Harbin/7/94. Molecular analysis demonstrated that our German 1996/1997 isolates differed by nine amino acids from B/Harbin/7/94 and represented a group of viruses that was completely different from the Harbin strain. Retrospective studies revealed the circulation of B/Yamanshi/166/98-like viruses in Germany already during the 1996/1997 season. Our results suggest that molecular analysis of the HA gene is important to complement the antigenic characterization for a better selection of appropriate vaccine strains.

Amino Acid Sequence↗

Some problems of molecular biology of poliovirus infection relevant to pathogenesis, viral spread and evolution.

Molecular mechanisms of poliovirus reproduction in the human gut remain largely unexplored. Nevertheless, there are grounds to believe that the virus spreads from cell to cell, like that from person to person during natural circulation, and involves a relatively small proportion of the highly heterogeneous viral population generated by the previous host. This mechanism of random sampling is responsible for the majority of fixed mutations, and contributes to the maintenance of a certain level of viral fitness (virulence). In the long term, random sampling may lead to the decrease in fitness and even to extinction of some viral evolutionary branches, explaining cases of self-limiting poliovirus infection in immunodeficient patients. A low propensity of the Sabin viruses for natural circulation may also be a related phenomenon. The trend to decrease in fitness may be interrupted by the appearance of rare, fitter (more virulent) variants, which may be responsible for poliomyelitis outbreaks caused by wild type virus, and for the development of paralytic disease in chronic carriers of the Sabin vaccine. All these evolutionary events are largely stochastic and hence are unpredictable in principle.

Digestive System↗

How evolution of mutations conferring drug resistance affects viral dynamics and clinical outcomes of cytomegalovirus-infected hematopoietic cell transplant recipients.

Infection with cytomegalovirus (CMV) remains a significant cause of morbidity and mortality among hematopoietic cell transplant (HCT) recipients. We describe two pediatric HCT recipients who developed persistent and severe drug-resistant CMV infections. CMV resistance to foscarnet and ganciclovir was detected after only 6 and 11 weeks of therapy, respectively. Viral pol mutations associated with drug resistance in these patients included T838A (a novel mutation) and D588N, which were shown by marker transfer to confer foscarnet and multidrug resistance, respectively. Each of these mutations significantly reduced in vitro replication of CMV, suggesting that they may decrease viral fitness. This finding was further supported by the disappearance of mutations upon withdrawal of antiviral pressure in one patient. Novel antivirals or combination therapy may be required for the treatment of drug-resistant CMV in HCT recipients and perhaps in other severely immunocompromised patients.

Adolescent↗

The evolution of viruses, the emergence of viral diseases: a synthesis that Martinus Beijerinck might enjoy.

The relentless production of viral variants and their selection for improved "fit" are seen from the perspective of the infectious disease sciences as ever-changing viral phenotypes and emerging disease risks. In the Darwinian cause:effect equation, we can characterize very well the effects of mutation and selection--these are catalogued as new viral phenotypes or pathotypes. However, the selective forces themselves driving such changes remain rather mysterious. Many selective forces must be at work, acting on the virus, the host, the host population and the environment. In some instances the virus seems to test new unoccupied niches in the absence of any apparent environmental change, but usually it is clear that changes are driven by human activity. Most important must be the ever increasing density of human, domestic animal and crop plant populations and the consequent increased opportunities for transmission of viral variants. Also important must be the great changes affecting all ecosystems--these especially favor the emergence of new zoonotic viruses and viral "species jumpers." The great increase in human travel and transport carries exotic viruses, vectors and hosts around the world, again favoring viral occupation of new niches. The rise of bioterrorism adds yet another threat. Increasing numbers of emerging viral disease episodes seem to be linked to a decline in global resources for proven public health programs, agricultural extension programs, and the like, programs that have stood in the way of the spread and evolution of viral pathogens. If the relationship between viral evolution and the emergence of new viral diseases is rooted firstly in the host and the host population, then more research and resources must be directed to intervention at these levels rather than at the level of the viruses themselves.

Animals↗

Secondary structure as a constraint on the evolution of a plant viral satellite RNA.

The genetic variability and evolution of the satellite RNA (satRNA) of cucumber mosaic virus (CMV) was analyzed. Twenty-five CMV-satRNAs compared clustered into three main groups, and no correlation was found between genetic proximity and other characteristics (pathogenicity, geographical origin) of the satRNAs. Values for the number of nucleotide substitutions per site between any two satRNAs suggest that divergence is checked by functional constraints. The analysis of mutations relative to an ancestral sequence, and the number of substitutions per site at first, second and third positions of codons in putative open reading frames, show that the variation of CMV-satRNAs does not follow a pattern typical of coding sequences, and indicates that preservation of the sequence of encoded products is not a constraint to evolution. On the other hand, when the observed variation was analyzed relative to a secondary structure model proposed for CMV-satRNAs, several lines of evidence indicated that the maintenance of the secondary structure is a constraint to evolution: the number of substitutions per site, the number of point insertions and deletions and the number of base substitutions that would disrupt base-pairing were significantly higher for unpaired than for base-paired positions. Also, compensatory mutations at base-paired positions occurred more frequently than expected from random. The results suggest that CMV-satRNAs are non-coding, functional RNAs whose biology would be determined by their direct interaction with components of the host and/or the helper virus.

Base Composition↗

Evolution of bovine viral diarrhea virus vaccines.

Control of bovine viral diarrhea virus (BVDV) infection is economically important to the cattle industry because the virus causes a variety of clinical diseases that adversely affect essentially all stages of the production cycle. Production losses primarily stem from reproductive failure and from immunosuppression during acute BVDV infection, which predisposes calves to respiratory or enteric diseases. Control is achieved by implementing herd health pro-grams focused on limiting exposure by avoiding persistently infected (PI) carrier cattle and by optimizing protective immunity through immunization. Vaccination cannot be relied upon solely to protect against fetal infection and losses due to BVD. This is because no single BVDV vaccine has been shown to give complete fetal protection. In addition to strategic use of vaccines, herd management practices should also be implemented to identify and eliminate PI carrier cattle and to avoid exposure to BVDV infection.

Animals↗

[Recurrence of hepatitis C virus (HCV) infection after liver transplantation for HCV-related disease: host factors and viral factors implicated in the occurrence and the severity of HCV recurrence].

Cirrhosis due to chronic infection by hepatitis C virus (HCV), associated or not to a primary hepatocarcinoma, has become the first indication of liver transplantation. Graft reinfection by HCV is considered to be systematic while its prognosis is variable from one patient to another. A better knowledge of factors implicated in the occurrence and severity of hepatitis C recurrence is crucial in order to make optimal patients' monitoring. This article aims to present available data in this field, clarifying the role of viral factors (viral load, genotype, evolution of viral quasispecies) and host-related factors (immune response) which could take part in the development of hepatitis C recurrence.

Carcinoma, Hepatocellular↗