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Background: We investigated the frequency of RAVs among patients failing to achieve SVR in two clinical trials. We also investigated the impact of interferon responsiveness on RAVs and specific baseline RAVs relationship with boceprevir treatment failure., Methods: Data are from 1020 patients enrolled into either SPRINT-2 or RESPOND-2; patients received a 4-week PR lead-in prior to receiving boceprevir or placebo. RAVs were analyzed via population-based sequence analysis of the NS3 protease gene (success rate of >90% at a virus level of ≥ 10,000IU/mL) RESULTS: The high SVR rate in patients who received boceprevir resulted in a low rate of RAVs; 7% was detected at baseline in all patients, which rose to 15% after treatment. However, RAVs were detected in 53% of patients that failed to achieve SVR, which declined to 22.8% 6-14 months following cessation of boceprevir therapy. Baseline RAVs alone were not predictive of virologic outcome; poor interferon responsiveness was highly predictive of non-SVR. RAVs were more frequently detected in poor interferon responders., Conclusions: We detected no association between the presence of baseline amino acid variants at boceprevir resistance-associated loci and outcome in the context of good IFN response., (© 2013 Elsevier Inc. All rights reserved.)

Background: Vaniprevir with P/R improved SVR rates over P/R alone in treatment-experienced patients with chronic HCV-genotype 1 infection, but treatment failure presents therapeutic challenges. We identified RAVs from non-cirrhotic patients failing to achieve SVR on vaniprevir-containing regimens from a dose/duration-ranging trial of triple-combination therapy., Methods: Using population analysis, resistance sequencing was performed on all baseline samples and on samples at virologic failure in the vaniprevir arms. Longitudinal clonal analyses were performed on viral isolates from six vaniprevir recipients experiencing breakthrough viremia., Results: Baseline RAVs were detected in two patients subsequently experiencing virologic failure. At virologic failure, the majority of RAVs had substitutions at R155, A156, or D168. Clonal analyses identified novel double/triple variants emerging with continuing vaniprevir dosing., Conclusions: RAVs were predominantly observed at R155, A156, and/or D168 during virologic failure on vaniprevir/P/R. Double/triple RAVs were identified in patients remaining viremic on triple therapy, suggesting evolution of resistance under selective pressure., (Copyright © 2013 Elsevier Inc. All rights reserved.)

For over 40 years, avian sarcoma and leukosis virus (ASLV)-receptor interactions have been employed as a useful model system to study the mechanism of retroviral entry into cells. Pioneering studies on this system focused upon the genetic basis of the differential susceptibilities of different lines of chickens to infection by distinct subgroups of ASLV. These studies led to the definition of three distinct autosomal recessive genes that were predicted to encode cellular receptors for different viral subgroups. They also led to the concept of viral interference, i.e. the mechanism by which infection by one virus can render cells resistant to reinfection by other viruses that use the same cellular receptor. Here, we review the contributions that analyses of the ASLV-receptor system have made in unraveling the mechanisms of retroviral entry into cells and focus on key findings such as identification and characterization of the ASLV receptor genes and the subsequent elucidation of an unprecedented mechanism of virus-cell fusion. Since many of the initial findings on this system were published in the early volumes of Virology, this subject is especially well suited to this special anniversary issue of the journal.

Purpose: Hypertension (HTN), hyperlipidemia (HLP), and hyperinsulinemia are known risk factors for the development of cardiovascular disease. Each has independently been shown to be associated with impaired endothelial function, as demonstrated by decreased endothelial derived relaxation (EDR). Previous work in our laboratory has shown that rats fed a high-fat sucrose (HFS) diet will become insulin resistant, hypertriglyceridemic, and hypertensive. We hypothesize that the development of these diet-induced risk factors is associated with endothelial dysfunction and a significant decrease in EDR. Furthermore, the endothelial dysfunction will be improved by returning to a normal (low-fat complex carbohydrate (LFCC)) diet., Methods: Adult, male Fischer rats were fed either a LFCC or a HFS diet for 6 months (n = 8 in each group). A third group of rats (SWITCH) was fed a HFS diet for 6 months and then changed to a LFCC diet for 4 weeks. Blood pressure was measured via the tail-cuff method weekly. The rats were sacrificed and aortic ring segments were placed in physiologic tissue baths for measurement of vascular reactivity to various agents. Arterial ring segments were constricted with potassium chloride (K) and phenylephrine (PE). Endothelial-dependent vasorelaxation was measured with acetylcholine (Ach), bradykinin (BK), and calcium ionophore (CA). Endothelial-independent relaxation was measured using sodium nitroprusside (NTP)., Results: The HFS diet group developed HTN compared to LFCC group. Vasoconstriction to K and PE were similar in all groups. Vasorelaxation to Ach, BK, and CA was significantly decreased in the HFS group, but returned to baseline in the diet-switched group, as did the systolic blood pressure. There were no differences in relaxation to NTP., Conclusions: HFS diet-induced HTN is associated with significantly decreased EDR. Switching to a low-fat diet reverses this effect. The vascular smooth muscle contraction and endothelial-independent relaxation are not affected by the diet-induced risk factors. There is a direct and reversible effect of an HFS diet on endothelial function and blood pressure., (Copyright 1999 Academic Press.)

The effect of a diet low in total fat and high in complex carbohydrates on the excretion of bile acids and neutral sterols and on serum lipids was studied in women, 46-47 years old, who were consuming a mixed Western diet. Participants kept an initial 3-day food record while consuming their normal diet (pre-diet period). During the dietary intervention period (experimental diet) which lasted for 26 days, all volunteers consumed a low-calorie, low-fat (less than 10% of total calories), high-fiber (37 g/day, high-carbohydrate diet. At the 1-year follow-up, the participants completed another 3-day food record, which indicates that these volunteers maintained their caloric and fat intake at levels slightly higher than the experimental diet, but lower than the pre-diet period. Individual 24-hr fecal samples for 2 days and blood samples were collected from the volunteers during each dietary period. Fecal samples were analyzed for neutral sterols and bile acids, and blood samples were analyzed to ascertain cholesterol and triglyceride levels. There were no significant differences in the excretion of neutral sterols between the dietary periods. Fecal secondary bile acids were significantly lower during the experimental and follow-up diet periods compared with the pre-test diet period. Serum cholesterol levels were significantly lower during the experimental and follow-up diet periods than during the pre-test diet period. These results suggest that switching from a high-fat, low-fiber diet to a low-fat, high-fiber diet can reduce the excretion of bile acids which are thought to be involved in the promotion of colon cancer.