S W Chou

..These data are consistent with minimal defects observed in cell culture, but are not consistent with an important role for UL27 in vivo. We conclude that UL27 is not required for viral replication in vivo...

..There is a potential for increased maribavir resistance in UL27-UL97 double mutants...

..UL146 and UL147, which encode CXC chemokine homologues are among these variable ORFs...

..Mutation of the amino terminal motif, which is involved in the inactivation of Rb, also renders the virus hypersensitive to the drug and suggests that the motif may play a role in its mechanism of action...

..Transfer into strain T2211 facilitates the phenotyping of newly observed mutations, combinations of mutations, and clinical CMV sequences without an accompanying viral isolate...

..These effects influence the phenotypic assay of drug susceptibility and suggest the possibility of therapeutically useful combinations of maribavir and cellular kinase inhibitors...

..The 3 UL97 mutations now known to confer MBV resistance are located upstream of UL97 mutations linked to ganciclovir resistance, closer to kinase domains that are associated with adenosine triphosphate binding and phosphotransfer...

..Bacterial artificial chromosome CMV clones containing pol mutation L845P were nonviable unless repaired with the wild-type sequence...

..The existence of viable pol D413A mutants may facilitate the selection of additional drug resistance mutations in vivo and the study of these mutations in vitro...

..So far, no UL97 mutations are known to confer resistance to both GCV and MBV...

..The levels of resistance conferred by specific mutations are variable, ranging from insignificant resistance to triple-drug resistance...

..Although the function of UL27 is unknown, it does not appear to be a direct antiviral target for MBV...

..This information should improve the interpretation of genotypic data generated by diagnostic laboratories...

..Recombinant phenotyping was performed to determine whether the previously uncharacterized genotypic changes affected ganciclovir susceptibility, especially in those receiving the longer duration of prophylaxis...

..Uncommon mutations M460T and C603R increased cyclopropavir EC(50)s by 8- to 10-fold...

..Cytomegalovirus UL54 DNA polymerase mutations observed in clinical specimens are of diagnostic significance if confirmed to affect antiviral drug susceptibility...

..Unlike GCV and CDV, exonuclease mutations are not a preferred mechanism of CPV resistance, but mutations in and near pol region III may confer CPV resistance by affecting its recognition as an incoming base for DNA polymerization...

..The UL27 sequence was well conserved in a sample of 16 diverse clinical isolates. Mutation in UL27, a betaherpesvirus-specific early gene of unknown biological function, may adapt the virus for growth in the absence of UL97 activity...

..Antiviral activities of foscarnet and cidofovir were unaffected by maribavir...

..6-fold increased ganciclovir resistance. Occurrence of the V809 mutation in 3 unrelated cases suggests that it is a clinically significant viral genetic marker for foscarnet resistance and decreased susceptibility to ganciclovir...

..The emergence of drug resistance may be reduced by optimization of host immunity, use of potent antiviral drug regimens, and adherence to dosing regimens that adequately suppress viral replication...

..Low drug levels resulting from oral GCV therapy may predispose the virus to the initial selection of these low-grade UL97 resistance mutations and to later accumulation of other mutations and greater resistance...

..This information may help in the selection of alternative therapy...

..A single mutation in region V of CMV pol can, therefore, confer multiple drug resistance in a clinical isolate...

..The recombinant virus was resistant to ganciclovir (8.4-fold increase in the 50% inhibitory concentration), was sensitive to foscarnet, and replicated normally in cell culture...

..Sequence alignments showed >98% interstrain homology and amino acid variation in only 4% of the 1, 237 codons. Almost all variation occurred outside of conserved functional domains where resistance mutations have been identified...

..This study significantly increases the number of confirmed CMV pol resistance mutations, at both conserved and nonconserved loci, with implications for molecular mechanisms and the genotypic diagnosis of antiviral resistance...

..Multicenter trials using combination therapy to identify factors predictive of response are needed in the subset of patients with progressive allograft injury...

..Artesunate treatment resulted in a 1.7-2.1-log reduction in viral load by treatment day 7, with a viral half-life of 0.9-1.9 days, indicating a highly effective block in viral replication...

..However, the finding of greater variability among treatment responders in the carboxy end of NS5A suggests that the V3 region merits further investigation...

..016). The incidence of foscarnet resistance after 6, 9, and 12 months of therapy was 13%, 24%, and 37%, respectively...

..Thus, Cdk1 is necessary and sufficient to drive pseudomitosis, whereas a combination of viral and cell cycle-regulated kinases is important during viral replication...

..We report on two allogeneic stem cell transplant recipients who developed cytomegalovirus disease associated with new viral mutations that conferred antiviral drug resistance...

..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...

..To examine the clinical significance of HIV protease mutations detected before and after therapy with amprenavir...

..The cytomegalovirus (CMV) UL97 inhibitor drug maribavir (MBV) is undergoing clinical antiviral trials...

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..The additive effect of multiple mutations on antiviral susceptibility suggests that increasing antiviral-resistant phenotypes can result from different virus-antiviral interactions...

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..These rates were similar among case patients and control subjects and were similar by risk group. The CMV gB2 genotype is not a major determinant of retinitis pathogenicity but appears to be highly prevalent among HIV-infected patients...

..The presence of mutational clusters provides insight into the complex mutational patterns required for HIV-1 protease inhibitor resistance...

..In this large case control analysis of patients undergoing liver transplantation for diverse etiologies, TNF promoter polymorphisms were not independently associated with rejection or survival...

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..We hypothesized that amino acid substitutions within critical T-cell epitopes could lead to increased severity of HCV disease...

..Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience. wiley.com/jpages/0270-9139/suppmat/index.html)...

..Most NRTI mutations group into one of three clusters, although several (e.g., M184V) occur in multiple mutational contexts...

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..W. Lawrence Drew (UCSF) and from Dr. Alejo Erice (University of Minnesota). ..

..Detailed understanding of the genetic mechanisms of resistance will improve the design of suitable new drug structures and antiviral targets. ..