9 results on '"Sheridan, David"'
Search Results
2. Maximum levels of hepatitis C virus lipoviral particles are associated with early and persistent infection.
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Sheridan, David A., Hajarizadeh, Behzad, Fenwick, Fiona I., Matthews, Gail V., Applegate, Tanya, Douglas, Mark, Neely, Dermot, Askew, Bev, Dore, Gregory J., Lloyd, Andrew R., George, Jacob, Bassendine, Margaret F., and Grebely, Jason
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HEPATITIS C treatment , *LIPOPROTEINS , *HEPATITIS C diagnosis , *BIOMARKERS , *MICROBIAL sensitivity tests , *ULTRACENTRIFUGATION - Abstract
Background & Aims Hepatitis C virus ( HCV) is bound to plasma lipoproteins and circulates as an infectious lipoviral particle ( LVP). Experimental evidence indicates that LVPs have decreased susceptibility to antibody-mediated neutralisation and higher infectivity. This study tested the hypothesis that LVPs are required to establish persistent infection, and conversely, low levels of LVP in recent HCV infection increase the probability of spontaneous HCV clearance. Methods LVP in non-fasting plasma was measured using the concentration of HCV RNA bound to large >100 n m sized lipoproteins after ex vivo addition of a lipid emulsion, that represented the maximum concentration of LVP (maxi- LVP). This method correlated with LVP in fasting plasma measured using iodixanol density gradient ultracentrifugation. Maxi- LVP was measured in a cohort of 180 HCV participants with recent HCV infection and detectable HCV RNA from the Australian Trial in Acute Hepatitis C ( ATAHC) and Hepatitis C Incidence and Transmission Study in prison ( HITS-p) cohorts. Results Spontaneous clearance occurred in 15% (27 of 180) of individuals. In adjusted analyses, low plasma maxi- LVP level was independently associated with spontaneous HCV clearance (≤827 IU/ml; adjusted odds ratio 3.98, 95% CI: 1.02, 15.51, P = 0.047), after adjusting for interferon lambda-3 rs8099917 genotype, estimated duration of HCV infection and total HCV RNA level. Conclusions Maxi- LVP is a biomarker for the maximum concentration of LVP in non-fasting samples. Low maxi- LVP level is an independent predictor of spontaneous clearance of acute HCV. [ABSTRACT FROM AUTHOR]
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- 2016
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3. Omega-3 fatty acids and/or fluvastatin in hepatitis C prior non-responders to combination antiviral therapy - a pilot randomised clinical trial.
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Sheridan, David A., Bridge, Simon H., Crossey, Mary M. E., Felmlee, Daniel J., Fenwick, Fiona I., Thomas, Howard C., Neely, R. Dermot G., Taylor‐Robinson, Simon D., and Bassendine, Margaret F.
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OMEGA-3 fatty acids , *FLUVASTATIN , *HEPATITIS C , *ANTIVIRAL agents , *CLINICAL trials - Abstract
Background & Aims Hepatitis C virus ( HCV) utilises cholesterol and lipoprotein metabolism for replication and infectivity. Statins and omega-3 (n-3) polyunsaturated fatty acids ( PUFA) have been shown to have antiviral properties in vitro. This open label pilot study evaluated the efficacy of fluvastatin (Lescol® 40-80 mg) and n-3 PUFA (Omacor®1 g and 2-4 g) on HCV- RNA and lipoviral particles ( LVP) in difficult to treat prior non-responders. Methods Patients ( n = 60) were randomly allocated in a factorial design to: no active drug; low-dose n-3 PUFA; high-dose n-3 PUFA; fluvastatin; low-dose n-3 PUFA + fluvastatin; or high-dose n-3 PUFA + fluvastatin. 50/60 completed study drugs for 12 weeks and followed up to week 24. Comparison was made between fluvastatin ( n = 24) vs no fluvastatin ( n = 26) and n-3 PUFA high-dose ( n = 17) vs low-dose ( n = 17) vs none ( n = 16). The primary outcomes were change in total HCV- RNA, LVP and ALT at week 12 compared with baseline. Secondary outcome was change in interferon-gamma-inducible protein-10 ( IP10) as a measure of interferon activation. Results 35% had compensated cirrhosis and 45% were prior null responders. There was no significant change in total HCV RNA, LVP, non-LVP or LVP ratio in patients receiving fluvastatin or n-3 PUFAs. ALT was not significantly different in those treated with fluvastatin or n-3 PUFAs. 12 weeks of low-dose n-3 PUFA decreased median IP10 concentration by −39 pg/ml (−111, 7.0 pg/ml Q1-Q3). Conclusions Fluvastatin and n-3 PUFAs have no effect on plasma HCV- RNA or LVP. The effect of low-dose n-3 PUFA on IP10 warrants further prospective evaluation as a supplemental therapy to enhance interferon sensitivity. [ABSTRACT FROM AUTHOR]
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- 2014
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4. Apolipoprotein-E and hepatitis C lipoviral particles in genotype 1 infection: Evidence for an association with interferon sensitivity
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Sheridan, David A., Bridge, Simon H., Felmlee, Daniel J., Crossey, Mary M.E., Thomas, Howard C., Taylor-Robinson, Simon D., Toms, Geoffrey L., Neely, R. Dermot G., and Bassendine, Margaret F.
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APOLIPOPROTEIN B , *APOLIPOPROTEIN E , *HEPATITIS C virus , *INTERFERONS , *SENSITIVITY analysis , *DENSITY gradient centrifugation , *ENZYME-linked immunosorbent assay , *LIPOPROTEINS - Abstract
Background & Aims: Hepatitis C virus (HCV) interacts with apolipoproteins B (apoB) and E (apoE) to form infectious lipoviral particles (LVP). Response to peginterferon is influenced by interferon-stimulated genes (ISGs) and IL28B genotype. LDL cholesterol (LDL-C) also predicts interferon response, therefore we hypothesised that LVP may also be associated with interferon sensitivity. Methods: LVP (HCV RNA density ⩽1.07g/ml) and ‘non-LVP’ (d >1.07g/ml) were measured in 72 fasted HCV-G1 patients by iodixanol density gradient ultracentrifugation and the LVP ratio (LVP/LVP+non-LVP) was calculated. Fasting lipid profiles and apolipoproteins B and E were measured. Interferon-gamma-inducible protein 10kDa (IP10), a marker of ISGs, was measured by ELISA. Results: Complete early virological response (EVR) was associated with lower apoE (23.9±7.7 vs. 36.1±15.3mg/L, p =0.013), higher LDL-C (p =0.039) and lower LVP ratios (p =0.022) compared to null responders. In multivariate linear regression analysis, apoE was independently associated with LVP (R2 19.5%, p =0.003) and LVP ratio (p =0.042), and negatively with LDL-C (p <0.001). IP10 was significantly associated with ApoB (p =0.001) and liver stiffness (p =0.032). IL28B rs12979860 CC was associated with complete EVR (p =0.044), low apoE (CC 28±11 vs. CT/TT 35±13mg/L, p =0.048) and higher non-LVP (p =0.008). Logistic regression analysis indicated that patients with high LVP ratios were less likely to have EVR (odds ratio 0.01, p =0.018). Conclusions: In HCV-G1, interferon sensitivity is characterised by low LVP ratios and low apoE levels in addition to higher LDL-C and IL28B rs12979860 CC. Null-response is associated with increased LVP ratio. The association of apoE and LVP with peginterferon treatment response suggests that lipid modulation is a potential target to modify interferon sensitivity. [Copyright &y& Elsevier]
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- 2012
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5. HCV and the hepatic lipid pathway as a potential treatment target
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Bassendine, Margaret F., Sheridan, David A., Felmlee, Daniel J., Bridge, Simon H., Toms, Geoffrey L, and Neely, R. Dermot G.
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HEPATITIS C virus , *LIPIDS , *ATHEROSCLEROSIS , *CARDIOVASCULAR diseases , *DIABETES , *IMMUNE system , *METABOLISM - Abstract
Atherosclerosis has been described as a liver disease of the heart . The liver is the central regulatory organ of lipid pathways but since dyslipidaemias are major contributors to cardiovascular disease and type 2 diabetes rather than liver disease, research in this area has not been a major focus for hepatologists. Virus–host interaction is a continuous co-evolutionary process involving the host immune system and viral escape mechanisms . One of the strategies HCV has adopted to escape immune clearance and establish persistent infection is to make use of hepatic lipid pathways. This review aims to: [•] update the hepatologist on lipid metabolism [•] review the evidence that HCV exploits hepatic lipid pathways to its advantage [•] discuss approaches to targeting host lipid pathways as adjunctive therapy. [ABSTRACT FROM AUTHOR]
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- 2011
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6. IL28B, HLA-C, and KIR Variants Additively Predict Response to Therapy in Chronic Hepatitis C Virus Infection in a European Cohort: A Cross-Sectional Study.
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Suppiah, Vijayaprakash, Gaudieri, Silvana, Armstrong, Nicola J., O'Connor, Kate S., Berg, Thomas, Weltman, Martin, Abate, Maria Lorena, Spengler, Ulrich, Bassendine, Margaret, Dore, Gregory J., Irving, William L., Powell, Elizabeth, Hellard, Margaret, Riordan, Stephen, Matthews, Gail, Sheridan, David, Nattermann, Jacob, Smedile, Antonina, Müller, Tobias, and Hammond, Emma
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GENOMICS ,HEPATITIS C virus ,INTERFERONS ,RIBAVIRIN ,INTERLEUKINS ,KILLER cells - Abstract
Background: To date, drug response genes have not proved as useful in clinical practice as was anticipated at the start of the genomic era. An exception is in the treatment of chronic hepatitis C virus (HCV) genotype 1 infection with pegylated interferon-alpha and ribavirin (PegIFN/R). Viral clearance is achieved in 40%-50% of patients. Interleukin 28B (IL28B) genotype predicts treatment-induced and spontaneous clearance. To improve the predictive value of this genotype, we studied the combined effect of variants of IL28B with human leukocyte antigen C (HLA-C), and its ligands the killer immunoglobulin-like receptors (KIR), which have previously been implicated in HCV viral control. Methods and Findings: We genotyped chronic hepatitis C (CHC) genotype 1 patients with PegIFN/R treatment-induced clearance (n = 417) and treatment failure (n = 493), and 234 individuals with spontaneous clearance, for HLA-C C1 versus C2, presence of inhibitory and activating KIR genes, and two IL28B SNPs, rs8099917 and rs12979860. All individuals were Europeans or of European descent. IL28B SNP rs8099917 ''G'' was associated with absence of treatment-induced clearance (odds ratio [OR] 2.19, p = 1.27×1028, 1.67-2.88) and absence of spontaneous clearance (OR 3.83, p = 1.71×10
-14 , 2.67-5.48) of HCV, as was rs12979860, with slightly lower ORs. The HLA-C C2C2 genotype was also over-represented in patients who failed treatment (OR 1.52, p = 0.024, 1.05-2.20), but was not associated with spontaneous clearance. Prediction of treatment failure improved from 66% with IL28B to 80% using both genes in this cohort (OR 3.78, p = 8.83×10-6 , 2.03-7.04). There was evidence that KIR2DL3 and KIR2DS2 carriage also altered HCV treatment response in combination with HLA-C and IL28B. Conclusions: Genotyping for IL28B, HLA-C, and KIR genes improves prediction of HCV treatment response. These findings support a role for natural killer (NK) cell activation in PegIFN/R treatment-induced clearance, partially mediated by IL28B. [ABSTRACT FROM AUTHOR]- Published
- 2011
7. IL28B is associated with response to chronic hepatitis C interferon-α and ribavirin therapy.
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Suppiah, Vijayaprakash, Moldovan, Max, Ahlenstiel, Golo, Berg, Thomas, Weltman, Martin, Abate, Maria Lorena, Bassendine, Margaret, Spengler, Ulrich, Dore, Gregory J., Powell, Elizabeth, Riordan, Stephen, Sheridan, David, Smedile, Antonina, Fragomeli, Vincenzo, Müller, Tobias, Bahlo, Melanie, Stewart, Graeme J., Booth, David R., and George, Jacob
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GENETIC research ,HEPATITIS C virus ,HEPATITIS C treatment ,INTERFERONS ,RIBAVIRIN ,GENOMES - Abstract
Hepatitis C virus (HCV) infects 3% of the world's population. Treatment of chronic HCV consists of a combination of PEGylated interferon-α (PEG-IFN-α) and ribavirin (RBV). To identify genetic variants associated with HCV treatment response, we conducted a genome-wide association study of sustained virological response (SVR) to PEG-IFN-α/RBV combination therapy in 293 Australian individuals with genotype 1 chronic hepatitis C, with validation in an independent replication cohort consisting of 555 individuals. We report an association to SVR within the gene region encoding interleukin 28B (IL28B, also called IFNλ3; rs8099917 combined P = 9.25 × 10
−9 , OR = 1.98, 95% CI = 1.57–2.52). IL28B contributes to viral resistance and is known to be upregulated by interferons and by RNA virus infection. These data suggest that host genetics may be useful for the prediction of drug response, and they also support the investigation of the role of IL28B in the treatment of HCV and in other diseases treated with IFN-α. [ABSTRACT FROM AUTHOR]- Published
- 2009
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8. Intravascular Transfer Contributes to Postprandial Increase in Numbers of Very-Low-Density Hepatitis C Virus Particles.
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Felmlee, Daniel J., Sheridan, David A., Bridge, Simon H., Nielsen, Søren U., Milne, Ross W., Packard, Chris J., Caslake, Muriel J., McLauchlan, John, Toms, Geoffrey L., Neely, R. Dermot G., and Bassendine, Margaret F.
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HEPATITIS C virus ,LOW density lipoproteins ,TRIGLYCERIDES ,METABOLISM ,BLOOD plasma ,CHRONIC active hepatitis ,APOLIPOPROTEINS ,GEL permeation chromatography - Abstract
Background & Aims: The physical association of hepatitis C virus (HCV) particles with lipoproteins in plasma results in distribution of HCV in a broad range of buoyant densities. This association is thought to increase virion infectivity by mediating cell entry via lipoprotein receptors. We sought to determine if factors that affect triglyceride-rich lipoprotein (TRL) metabolism alter the density and dynamics of HCV particles in the plasma of patients with chronic HCV infection. Methods: Fasting patients (n = 10) consumed a high-fat milkshake; plasma was collected and fractionated by density gradients. HCV- RNA was measured in the very-low-density fraction (VLDF, d < 1.025 g/mL) before and at 7 serial time points postprandially. Results: The amount of HCV RNA in the VLDF (HCV
VLDF ) increased a mean of 26-fold, peaking 180 minutes after the meal (P < .01). Quantification of HCV RNA throughout the density gradient fractions revealed that HCVVLDF rapidly disappeared, rather than migrating into the adjacent density fraction. Immuno-affinity separation of the VLDF, using antibodies that recognize apolipoprotein B–100 and not apolipoprotein B–48, showed that HCVVLDF is composed of chylomicron- and VLDL-associated HCV particles; peaking 120 and 180 minutes after the meal, respectively. Plasma from fasting HCV-infected patients mixed with uninfected plasma increased the quantity of HCVVLDF , compared with that mixed with phosphate-buffered saline, showing extracellular assembly of HCVVLDF . Conclusions: Dietary triglyceride alters the density and dynamics of HCV in plasma. The rapid clearance rate of HCVVLDF indicates that association with TRL is important for HCV infectivity. HCV particles, such as exchangeable apolipoproteins, appear to reassociate with TRLs in the vascular compartment. [ABSTRACT FROM AUTHOR]- Published
- 2010
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9. IL28B is associated with response to chronic hepatitis C interferon-α and ribavirin therapy
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Vijayaprakash Suppiah, Tobias Müller, Max Moldovan, Maria Lorena Abate, Margaret F. Bassendine, David Sheridan, Martin Weltman, Ulrich Spengler, Jacob George, Melanie Bahlo, Thomas Berg, Vincenzo Fragomeli, Gregory J. Dore, Antonina Smedile, Elizabeth E. Powell, Stephen M. Riordan, Graeme J. Stewart, David R. Booth, Golo Ahlenstiel, Suppiah, Vijayaprakash, Moldovan, Max, Ahlenstiel, Golo, Berg, Thomas, Weltman, Martin, Abate, Maria Lorena, Bassendine, Margaret, Spengler, Ulrich, Dore, Gregory J, Powell, Elizabeth, Riordan, Stephen, Sheridan, David, Smedile, Antonina, Fragomeli, Vincenzo, Muller, Tobias, Bahlo, Melanie, Stewart, Graeme J, Booth, David R, and George, Jacob
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ribavirin ,Hepatitis C virus ,Population ,drug response ,Alpha interferon ,Biology ,PEGylated interferon-alpha ,medicine.disease_cause ,chemistry.chemical_compound ,Interferon ,Genetics ,medicine ,Interleukin 28 ,education ,education.field_of_study ,Ribavirin ,virus diseases ,Hepatitis C ,medicine.disease ,Virology ,digestive system diseases ,Interleukin 28B ,chemistry ,Immunology ,gene expression ,antiviral activity ,hepatitis C ,medicine.drug - Abstract
Hepatitis C virus (HCV) infects 3% of the world's population. Treatment of chronic HCV consists of a combination of PEGylated interferon-alpha (PEG-IFN-alpha) and ribavirin (RBV). To identify genetic variants associated with HCV treatment response, we conducted a genome-wide association study of sustained virological response (SVR) to PEG-IFN-alpha/RBV combination therapy in 293 Australian individuals with genotype 1 chronic hepatitis C, with validation in an independent replication cohort consisting of 555 individuals. We report an association to SVR within the gene region encoding interleukin 28B (IL28B, also called IFNlambda3; rs8099917 combined P = 9.25 x 10(-9), OR = 1.98, 95% CI = 1.57-2.52). IL28B contributes to viral resistance and is known to be upregulated by interferons and by RNA virus infection. These data suggest that host genetics may be useful for the prediction of drug response, and they also support the investigation of the role of IL28B in the treatment of HCV and in other diseases treated with IFN-alpha.
- Published
- 2009
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