Dataset Information

Phenotypic analysis of NS5A variant from liver transplant patient with increased cyclosporine susceptibility.

ABSTRACT: Hepatitis C virus (HCV) replication is limited by cyclophilin inhibitors but it remains unclear how viral genetic variations influence susceptibility to cyclosporine (cyclosporine A, CsA), a cyclophilin inhibitor. In this study HCV from liver transplant patients was sequenced before and after CsA exposure. Phenotypic analysis of NS5A sequence was performed by using HCV sub genomic replicon to determine CsA susceptibility. The data indicates an atypical proline at position 328 in NS5A causes increases CsA sensitivity both in the context of genotype 1a and 1b residues. Point mutants mimicking other naturally occurring residues at this position also increased (Ala) or decreased (Arg) replicon sensitivity to CsA relative to the typical threonine (genotype 1a) or serine (genotype 1b) at this position. This work has implications for treatment of HCV by cyclophilin inhibitors.

SUBMITTER: Ansari IU

PROVIDER: S-EPMC3761804 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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Phenotypic analysis of NS5A variant from liver transplant patient with increased cyclosporine susceptibility.

Ansari Israr-Ul H IU Allen Todd T Berical Andrew A Stock Peter G PG Barin Burc B Striker Rob R

Virology 20130102 2

Hepatitis C virus (HCV) replication is limited by cyclophilin inhibitors but it remains unclear how viral genetic variations influence susceptibility to cyclosporine (cyclosporine A, CsA), a cyclophilin inhibitor. In this study HCV from liver transplant patients was sequenced before and after CsA exposure. Phenotypic analysis of NS5A sequence was performed by using HCV sub genomic replicon to determine CsA susceptibility. The data indicates an atypical proline at position 328 in NS5A causes incr ...[more]

PMID: 23290631

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Project description:UnlabelledAfrican trypanosomes, except Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense, which cause human African trypanosomiasis, are lysed by the human serum protein apolipoprotein L1 (ApoL1). These two subspecies can resist human ApoL1 because they express the serum resistance proteins T. b. gambiense glycoprotein (TgsGP) and serum resistance-associated protein (SRA), respectively. Whereas in T. b. rhodesiense, SRA is necessary and sufficient to inhibit ApoL1, in T. b. gambiense, TgsGP cannot protect against high ApoL1 uptake, so different additional mechanisms contribute to limit this uptake. Here we report a complex interplay between trypanosomes and an ApoL1 variant, revealing important insights into innate human immunity against these parasites. Using whole-genome sequencing, we characterized an atypical T. b. gambiense infection in a patient in Ghana. We show that the infecting trypanosome has diverged from the classical T. b. gambiense strains and lacks the TgsGP defense mechanism against human serum. By sequencing the ApoL1 gene of the patient and subsequent in vitro mutagenesis experiments, we demonstrate that a homozygous missense substitution (N264K) in the membrane-addressing domain of this ApoL1 variant knocks down the trypanolytic activity, allowing the trypanosome to avoid ApoL1-mediated immunity.ImportanceMost African trypanosomes are lysed by the ApoL1 protein in human serum. Only the subspecies Trypanosoma b. gambiense and T. b. rhodesiense can resist lysis by ApoL1 because they express specific serum resistance proteins. We here report a complex interplay between trypanosomes and an ApoL1 variant characterized by a homozygous missense substitution (N264K) in the domain that we hypothesize interacts with the endolysosomal membranes of trypanosomes. The N264K substitution knocks down the lytic activity of ApoL1 against T. b. gambiense strains lacking the TgsGP defense mechanism and against T. b. rhodesiense if N264K is accompanied by additional substitutions in the SRA-interacting domain. Our data suggest that populations with high frequencies of the homozygous N264K ApoL1 variant may be at increased risk of contracting human African trypanosomiasis.

Project description:BackgroundNon-alcoholic steatohepatitis (NASH) is the second-leading indication for liver transplantation (LT) worldwide and is projected to become the leading indication. Our study aimed to determine clinical variables that predict post-LT survival in NASH.MethodsA systematic review and meta-analysis was performed. On June 18, 2020 and April 28, 2022, Ovid MEDLINE ALL, Ovid Embase, Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Trials were searched. No date limits were applied. Inclusion criteria specified the type of study and our study's population/comparison and outcome/timepoints. Pediatric, animal, retransplantation-only, and studies classifying cryptogenic cirrhosis patients with body mass index (BMI) <30 as NASH were excluded. Studies with duplicate cohorts and missing information were excluded from the meta-analysis. Studies were appraised using the Newcastle-Ottawa Scale. This study was preregistered in PROSPERO (CRD42020196915).FindingsOut of 8583 studies identified, 25 studies were included in the systematic review, while 5 studies were included in the meta-analysis. Our quantitative review suggested that the following variables were predictive of post-LT NASH patient survival: recipient age, functional status, pre-LT hepatoma, model for end-stage liver disease (MELD) score, diabetes mellitus (DM), pre-LT dialysis, hepatic encephalopathy, portal vein thrombosis, hospitalization/ICU at LT, and year of LT. Predictors of graft survival included recipient age, BMI, pre-LT dialysis, and DM. Our pooled meta-analyses included five predictors of patient survival. Increased patient mortality was associated with older recipient age (HR=2·07, 95%CI: 1·71-2·50, I2=0, τ2=0, p=0·40) and pretransplant DM (HR=1·18, 95%CI: 1·08-1·28, I2=0, τ2=0, p=0·76).InterpretationOur systematic review and meta-analysis aimed to synthesise predictive variables of mortality in LT NASH patients. Clinically, this might help to identify modifiable risk factors that can be optimized in the post-transplant setting to improve patient outcomes and optimises decision making in the resource-limited LT setting.FundingToronto General and Western Hospital Foundation.

Dataset Information

Phenotypic analysis of NS5A variant from liver transplant patient with increased cyclosporine susceptibility.

Publications

Phenotypic analysis of NS5A variant from liver transplant patient with increased cyclosporine susceptibility.

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