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Factors in the emergence of infectious diseases.

"Emerging" infectious diseases can be defined as infections that have newly appeared in a population or have existed but are rapidly increasing in incidence or geographic range. Among recent examples are HIV/AIDS, hantavirus pulmonary syndrome, Lyme disease, and hemolytic uremic syndrome (a foodborne infection caused by certain strains of Escherichia coli). Specific factors precipitating disease emergence can be identified in virtually all cases. These include ecological, environmental, or demographic factors that place people at increased contact with a previously unfamiliar microbe or its natural host or promote dissemination. These factors are increasing in prevalence; this increase, together with the ongoing evolution of viral and microbial variants and selection for drug resistance, suggests that infections will continue to emerge and probably increase and emphasizes the urgent need for effective surveillance and control. Dr. David Satcher's article and this overview inaugurate Perspectives, a regular section in this journal intended to present and develop unifying concepts and strategies for considering emerging infections and their underlying factors. The editors welcome, as contributions to the Perspectives section, overviews, syntheses, and case studies that shed light on how and why infections emerge, and how they may be anticipated and prevented.

Agriculture↗

Revisiting Papillomavirus Taxonomy: A Proposal for Updating the Current Classification in Line with Evolutionary Evidence.

Papillomaviruses infect a wide array of animal hosts and are responsible for roughly 5% of all human cancers. Comparative genomics between different virus types belonging to specific taxonomic groupings (e.g., species, and genera) has the potential to illuminate physiological differences between viruses with different biological outcomes. Likewise, extrapolation of features between related viruses can be very powerful but requires a solid foundation supporting the evolutionary relationships between viruses. The current papillomavirus classification system is based on pairwise sequence identity. However, with the advent of metagenomics as facilitated by high-throughput sequencing and molecular tools of enriching circular DNA molecules using rolling circle amplification, there has been a dramatic increase in the described diversity of this viral family. Not surprisingly, this resulted in a dramatic increase in absolute number of viral types (i.e., sequences sharing <90% L1 gene pairwise identity). Many of these novel viruses are the sole member of a novel species within a novel genus (i.e., singletons), highlighting that we have only scratched the surface of papillomavirus diversity. I will discuss how this increase in observed sequence diversity complicates papillomavirus classification. I will propose a potential solution to these issues by explicitly basing the species and genera classification on the evolutionary history of these viruses based on the core viral proteins (E1, E2, and L1) of papillomaviruses. This strategy means that it is possible that a virus identified as the closest neighbor based on the E1, E2, L1 phylogenetic tree, is not the closest neighbor based on L1 nucleotide identity. In this case, I propose that a virus would be considered a novel type if it shares less than 90% identity with its closest neighbors in the E1, E2, L1 phylogenetic tree.

Animals↗

[The recommendations of GESIDA/SEFH/PNS for improving adherence to antiretroviral treatment. AIDS Study Group of the Spanish Society of Hospital Pharmacy and the National Plan on AIDS of the Minister of Health and Consumers].

The main objective of HAART is to achieve a complete suppression of the viral replication for long time. However, when the therapeutic drug levels are low, HIV can replicate and it can develop resistances. This fact can be the reason of treatment failure, HIV transmission of resistant strains and therefore an inappropriate use of the economical resources. In order to get the adequate therapeutic drug levels it is necessary to have a good adherence to the treatment. We review the factors that influence the adherence, the evaluation methods and we recommend the possible intervention strategies which should be given by a multidisciplinary team, integrated by physicians, pharmacists, nurses, psychologists and other personal support. To start HAART is not an emergency. For this reason is very important to prepare to the patient and to identify the non-adherence factors in order to correct it. Once the HAART is indicated it is very important to offer information during the medical prescription and when the drugs are dispensed. During the therapy is necessary to follow actively all patients on HAART. In order to make therapeutical decisions we need to know the patient drug adherence rate. We recommend to use several methods to calculate the drug adherence rate, being the most commonly used the patient interview, the patient questionnaire, the refill count, the pharmacy visits rate together with the viral load evolution of the patient. In order to get all this information it is necessary to have a very good communication between all the people involved in HIV infected patients care. If non-adherence is detected it is necessary to start the intervention strategies to correct it and if they fail it might be necessary in some cases to stop HAART. The potential benefits of the adherence programs can justify the economical spend in human and hospital facilities resources.

Anti-HIV Agents↗

[Interferon alfa 2b treatment decreases histological activity in children with chronic hepatitis B].

Interferon alfa (IFN-alpha) is the only approved treatment for chronic hepatitis B (HBV) infection. In a non-controlled study 33 pediatric patients infected with HBV and in chronic phase of the disease were included and treated with 3 to 5 x 10(6) IU/m2 body surface of Interferon alpha 2b, 3 times per week, during 4 months. The objective was to evaluate the efficacy of the treatment in terms of the histological, biochemical and viral markers evolution of the patients. The patients were evaluated carrying out determinations of alanine aminotransferase (ALAT), HBsAg and HBeAg before treatment, at the end of the treatment and every 4 months during one year of follow-up. Liver biopsy and Knodell index determination were carried out at the beginning and upon concluding the follow-up. 39.3% of the patients concluded the treatment with normal ALAT values; 7% became HBsAg negative and 14.3% became HBsAg negative. These values ascended after follow-up to 51.5%, 11% and 37.5% respectively. The histological analysis evidenced a decrease of the Knodell index in 69% of the patients, an increase in 14.2%, and 13.8% did not show variation. Correlating the biochemical and histological responses, a favorable outcome was obtained in 36.4% of the patients, evidencing a remarkable reduction of the hepatic cytolysis. The treatment was well tolerated, being the fever the most frequent adverse events. The results confirm that interferon alfa seems to be an effective treatment for children with chronic hepatitis B.

Alanine Transaminase↗

[Studies on the basis of molecular biology of the phase change of influenza A(H3N2) viruses].

The analysis of nucleotide sequences on HA1 domain of 35 strains of influenza A(H3N2) virus showed that their HA1 genes all were 984 nucleotides in length coding for a HA1 protein with 328 amino acids and there was not any occurrence of insertion or deletion of nucleotides on HA1 genes among them. The appearance of "O" phase strain of influenza A (H3N2) virus was closely related with substitution at 226 position of amino acid on HA1 protein molecule and the three-dimensional structural change of HA protein. The results in this paper indicated that the positions with multiple changes on HA1 protein molecule located at the top of HA protein, especially at antigenic determinant B site or receptor binding site. These further demonstrated that the substitution of amino acid on HA1 protein molecule was caused mainly by suppress of herd immunity. This study also showed that the position of the cysteine and proline residues on the HA1 protein molecule were conservative and that the glycosylation sites located at N and C terminals, especially at N terminal of the HA1 protein The significance of such a distribute delta of glycosylation sites in the evolution of viral genes and epidemiology still remain unknown.

Amino Acid Sequence↗

HIV evolutionary dynamics within and among hosts.

The HIV evolutionary processes continuously unfold, leaving a measurable footprint in viral gene sequences. A variety of statistical models and inference techniques have been developed to reconstruct the HIV evolutionary history and to investigate the population genetic processes that shape viral diversity. Remarkably different population genetic forces are at work within and among hosts. Population-level HIV phylogenies are mainly shaped by selectively neutral epidemiologic processes, implying that genealogy-based population genetic inference can be useful to study the HIV epidemic history. Such evolutionary analyses have shed light on the origins of HIV, and on the epidemic spread of viral variants in different geographic locations and in different populations. The HIV genealogies reconstructed from within-host sequences indicate the action of selection pressure. In addition, recombination has a significant impact on HIV genetic diversity. Accurately quantifying both the adaptation rate and the population recombination rate of HIV will contribute to a better understanding of immune escape and drug resistance. Characterizing the impact of HIV transmission on viral genetic diversity will be a key factor in reconciling the different population genetic processes within and among hosts.

Adaptation, Biological↗

Oncogenes and human neoplasia.

Genes whose products are directly involved in the transformation of a normal to a neoplastic cell are present in most but not all oncogenic RNA viruses (retroviruses) have genes found in oncogenic RNA viruses (retroviruses) have also been found in normal cells, their coding sequences highly conserved in evolution. Such viral genes (v-onc) are expressed at high levels in infected cells. "Activation" of cellular homologues of v-onc genes (c-onc) may occur by a variety of mechanisms leading to an abnormal and/or increased expression of such activated c-onc genes in malignant cells. Although oncogene activation appears to be a critical step in the neoplastic transformation induced by oncogenic viruses, the role of this process in the development of chemical and radiation-induced neoplasia is not yet clear.

Cell Transformation, Neoplastic↗

Persistent acute hepatitis, an evolutive modality of the acute viral hepatitis, with high cirrhogenic potential.

An early detection of the progress to chronic stages of the acute diseases has particular pathogenic and therapeutic implications in hepatology. A complex clinical, biologic and morphologic study has been carried out in 86 patients with persistent acute hepatitis, recently released after 4-8 weeks of hospitalization for acute viral hepatitis, who were submitted to sequential investigations and follow up for a mean period of 16 months (range 2-24 months). All the patients have shown signs of activity of the liver injury, more than three months after the viral hepatitis onset (GOT/GPT 134 +/- 41 KU/219 +/- 59 KU, gammaglobulins 24.2 +/- 2.4%) and a characteristic immune pattern. In some cases, the morphologic investigations (endo-histologic and infrastructural) have revealed elements of acute and chronic active hepatitis. In 70% of the case the disease had a favourable course, while 30% of them showed a tendency to chronicization and even to cirrhosis, within a period of two years.

Biopsy↗

[Structural characteristics of four long terminal repeats (LTR) of human endogenous retroviruses and features of their integration sites].

Four LTR-containing regions of human chromosome 19 were sequenced by the primer walking technique using strings of short oligonucleotides tightly bound to the template. A comparative and evolutionary analysis of sequences homologous to human endogenous retroviruses (HERV) was performed, and the prototypes of the LTRs were determined. Analysis of the chromosome 19 sequences adjacent to LTR revealed that LTRs of HERV-K share a common location with other retroposons.

Base Sequence↗

Evolution rate of hepatitis delta virus RNA isolated in Taiwan.

The complete RNA sequences of hepatitis delta viruses (HDV) isolated at 3 years apart from a chronic delta hepatitis patient in Taiwan were determined. The sequence analysis showed an overall evolution rate of 3.18 x 10(-3) substitutions/nucleotide/year. The evolution rates in different parts of HDV RNA varied. The hypervariable region evolved faster (4.55 x 10(-3) substitutions/nucleotide/year) than the hepatitis delta antigen (HDAg)-coding region (2.60 x 10(-3) substitutions/nucleotide/year) and the autocatalytic region (1.11 x 10(-3) substitutions/nucleotide/year). These data are compatible with the previous finding that the hypervariable region is more divergent than the HDAg-coding region and the autocatalytic regions among the HDV isolates from different geographic areas. No substitution was found in the four previously identified conserved domains of HDV RNA, further confirming their functional importance in viral replication. The evolution rate of this HDV RNA is higher than that determined from the partial RNA sequences of two Japanese HDV isolates and similar to that found in a Lebanon isolate. Further, it was found that this HDV RNA retained the same microheterogeneities at 15 nucleotide positions detected in the RNA 3 years earlier. It is concluded that HDV RNA in patients' serum is extremely heterogeneous, and that the nucleotide substitutions in certain nucleotide positions likely have conferred evolutionary advantages for HDV. Viral sequence evolution is a possible mechanism for chronic HDV infection.

Adult↗

The effect of alcohol ingestion on the susceptibility of mice to viral infections.

The influence of acute alcoholization on the evolution of different viral diseases was studied in orally alcoholized mice. Ethanol increased mice susceptibility to encephalomyocarditis and influenza only when it was administered after virus infection. There was no dose-effect correlation. Vaccinia and Herpes virus infections were not modified by alcoholization. Hypotheses concerning the mechanisms of alcohol action were put forward.

Animals↗

Changes in viral loads of lamivudine-resistant mutants and evolution of HBV sequences during adefovir dipivoxil therapy.

The addition of adefovir dipivoxil (ADV) to ongoing lamivudine therapy is effective against lamivudine-resistant virus in patients with hepatitis B virus (HBV) infection. We studied 39 patients who received ADV added to lamivudine for breakthrough hepatitis. We determined early viral changes (12 weeks) in YMDD mutants (rtM204I [YIDD sequence], rtM204V [YVDD]) and rtL180M in all 39 patients as well as amino acid changes in the polymerase reverse transcriptase (rt) region and precore/core promoter mutations in 15 patients who received long-term treatment (more than 1 year). Changes in rtM204I and rtL180M viral loads were greater than that of the rtM204V, albeit statistically insignificant. Moreover, the greatest change in viral load was seen for rtM204I without hepatitis B e antigen (HBeAg). The precore mutant was replaced with wild-type virus in three of eight patients after 1 year of added ADV therapy. Compared to baseline with lamivudine therapy only, new amino acid mutations were seen in the rt region at baseline with ADV in seven patients. At 1 year after ADV coadministration, the YMDD motif was replaced with wild-type (rt204M) in two patients, in whom mutations were fewer and of a different type. We conclude that the rtM204I may be more sensitive to ADV in vivo. ADV tended to select wild-type virus from precore mutants. Moreover, viruses that were wild-type in the rt region reappeared after 1 year of ADV coadministration in some patients.

Adenine↗