Effect Of Hepatitis C Virus Infection Research Articles

Bile acid dysmetabolism in the gut-microbiota-liver axis under hepatitis C virus infection.

We recently analysed and reported the features of the micro biome under hepatitis C virus (HCV) infection, but the effect of HCV infection on bile acid (BA) metabolism in the gut-liver axis remains poorly understood. The aim of this study was to clarify the characteristics of the gut-liver axis in HCV-infected patients. The faecal BAs composition and gut microbiota from 100 chronic hepatitis C (CHC) patients were compared with those from 23 healthy individuals. For transcriptional analysis of the liver, 22 mild CHC (fibrosis stages [F] 0-2) and 42 advanced CHC (F3-4) cases were compared with 12 healthy individuals. The findings were confirmed using chimeric mice with human hepatocytes infected with HCV HCR6. Chronic hepatitis C patients, even at earlier disease stages, showed BA profiles distinct from healthy individuals, in which faecal deoxycholic acid (DCA) was significantly reduced and lithocholic acid or ursodeoxycholic acid became dominant. The decrease in faecal DCA was correlated with reduction in commensal Clostridiales and increase in oral Lactobacillales. Impaired biosynthesis of cholic acid (CA) was observed as a reduction in the transcription level of cytochrome P450 8B1 (CYP8B1), a key enzyme in CA biosynthesis. The reductions in faecal DCA and liver CYP8B1 were also observed in HCV-infected chimeric mice. Chronic hepatitis C alters the intestinal BA profile, in association with the imbalance of BA biosynthesis, which differs from the pattern in NAFLD. These imbalances appear to drive disease progression through the gut-microbiome-liver axis.

Prevalence and risk factors for hepatitis c virus co-infection among human immunodeficiency virus-infected patients and effect of hepatitis c virus infection on acquired immunodeficiency syndrome cases at baseline.

Background:Hepatitis C virus (HCV) co-infection with human immunodeficiency virus (HIV) exists as both viruses have the common routes of transmission. HIV infection has adverse effect on the natural history of HCV infection; however, the effect of HCV infection on the natural history of HIV infection is unclear.Materials and Methods:This study was cross-sectional comprising of treatment-naïve adult HIV-infected patients attending clinics at Usmanu Danfodiyo University Teaching Hospital, Sokoto and Specialist Hospital Sokoto. The study participants were screened for HCV anti]body and assayed for transaminases and CD4+ T-lymphocytes count levels. The symptoms of acquired immunodeficiency syndrome (AIDS)-defining illnesses were asked among the study participants. The questionnaire was used for the collection of data, and SPSS software version 20 was used for the analysis of data. Student's t-tests, Pearson’s, Chi-square, and Fisher's exact tests were used for the statistical analysis, and P < 0.05 was considered statistically significant.Results:The prevalence of HIV/HCV co-infection was 20.6%. Self-intravenous drugs usage was not statistically significant (P = 0.210). HIV mono-infected patients had significantly lower alanine aminotransferase levels compared to HIV/HCV co-infected study participants (P = 0.048). AIDS status at the baseline was comparable between HIV mono-infected and HIV/HCV co-infected study participants. (P = 0.227; 0.200; 0.130).Conclusion:Moderately high prevalence of HIV/HCV co-infection was observed in the current study. HCV co-infection had no effect on AIDS status at baseline. There is a need for routine screening of HCV infection in HIV-infected individuals.

Hepatitis C Virus Infection and Chemotherapy in Breast Cancer: A Retrospective Chart Analysis.

Breast cancer and hepatitis C virus (HCV) infection are major health problems in the U.S. Despite these highly prevalent diseases, there is limited information on the effect of HCV infection among patients with breast cancer receiving chemotherapy and the potential challenges they face during treatment. Currently, there are no guidelines for chemotherapy administration in HCV-positive patients with breast cancer. We performed a retrospective case-control analysis on six patients with breast cancer with active HCV infection and 12 HCV-negative matched controls who received chemotherapy between January 2000 and April 2015. We investigated dose delays, dose changes, hospitalization, hematologic reasons for dose delays, and variation in blood counts during chemotherapy from the patients' medical records. Fisher's exact test was used for statistical comparison of the outcome variables between the two groups. When compared with the HCV-negative patients, the HCV-positive group was at a significantly higher risk of dose delays (100% vs. 33%, p value .013), dose changes (67% vs. 8%, p value .022), hospitalization during chemotherapy (83% vs. 25%, p value .043), and hematotoxicity related dose delays (83% vs. 8%, p value .003). HCV-positive patients took a longer time to complete treatment than the HCV-negative group. Patients with HCV receiving chemotherapy for breast cancer are more likely to experience complications such as dose delays, dose modifications, and hospitalization. Future studies to confirm our findings and investigate on the effect of concurrent HCV and breast cancer treatment are warranted. This study found that hepatitis C infection is associated with a greater risk of treatment delays and dose modifications in patients with breast cancer receiving cytotoxic chemotherapy. Hepatitis C-positive patients have a higher treatment burden with dose changes, hospitalizations, and longer treatment periods than noninfected patients. Further prospective investigations to confirm these findings are warranted in a larger patient population. Given that hepatitis C infection can be curable with direct-acting antivirals, treatment of hepatitis C may alleviate treatment challenges during chemotherapy and improve survival for patients with breast cancer.

Chronic Hepatitis C Infection Has No Effect on Peripheral CD4+CD25+ Tregulatory Cells in Patients with End-Stage Renal Disease

ABSTRACTBackground: T regulatory cells (Tregs), through variable mechanisms, play a crucial role in Hepatitis C virus (HCV) chronicity and infection tolerance. A great speculation is posed regarding the level, role of Tregs in end-stage renal disease (ESRD), and the presence of associated factors that could influence the Tregs population. Accordingly, we aimed at studying the effect of HCV infection on peripheral CD4+CD25+Tregs population among patients on hemodialysis (HD) as well as the effect of other comorbidities on these cells.Patients and methods: A group of 77 patients on HD (32 were HD HCV+ and 45 were HD HCV−) and 80 healthy controls (HCs) were included in the study. Flow cytometric analysis was performed for identification and quantification of peripheral CD4+ CD25+Tregs.Results: The frequency of CD4+ CD25+Tregs increased significantly in HD patients compared to the HCs (p = <.0001 each). HCV posed no effect on peripheral CD4+ CD25+ Tregs in ESRD patients, when comparing HD HCV- and HD HCV+ groups. In the hypertensive HD HCV-, Tregs percentage was higher than that in the non-hypertensive. However, the difference was not statistically significant. No significant difference was detected between HD HCV- and HD HCV+ patients on the count and percentages of Tregs according to the duration of dialysis.Conclusion: Demonstrating that chronic HCV infection has no effect on CD4+ CD25+ Tregs cells levels in ESRD patients is of great importance to the success of future allografts in such patients.

Рossibilities of antitumor treatment of breast cancer рatients infected with heрatitis C virus

The objective: analysis of the results, allowing to form an opinion on the significance of different subclinical forms of the infection of the hepatitis C virus (HCV) in patients with breast cancer (BC).Materials and methods. Three clinico-laboratory observations were conducted, in which the effect of HCV infection on the incidence and severity of complications arising after using various methods of antitumor treatment was examined. In the first of them, the effect of infection on complications of surgical operations (SO) was studied, in the second – the effect of infection on the radiation reactions arising after radiation therapy (RT), and in the third – its effect on the adverse toxic effects of chemotherapy (CT).Results. It was found that the inapparant form of infection virtually did not effect the complications of CT and adverse side effects of both RT and HT. In the same time, the presence of the hyperfermentemic form of this infection was accompanied by an increase in the frequency of registration of complications and side effects of all methods of treatment of these patients.The conclusion. Patients, who are infected with the hepatitis C virus, who do not have signs of subclinical liver dysfunction can undergo surgical operations and prescribe radiotherapy or chemotherapy with almost no restrictions, since the risk of developing all these manifestations does not differ from that of uninfected patients.

Abnormal phenotypic features of IgM+B cell subsets in patients with chronic hepatitis C virus infection.

Hepatitis C virus (HCV) infection is associated with B cell abnormality; however the phenotypic profiles of immunoglobulin (Ig)M+B cell subsets in patients with HCV infection remain unclear. In the current study, the effect of HCV infection on IgM+B cell subsets was evaluated. The percentages, as well as the differentiation and activation features of peripheral IgM+B naive subsets [cluster of differentiation (CD)27-IgM+B cells] and IgM+B memory subsets (CD27+IgM+B cells) were assessed using flow cytometry in 27 patients with chronic hepatitis C (CHC) and 20 healthy controls (HCs). The frequency of CD27+IgM+B memory subsets detected in patients with CHC was significantly higher than that in HCs (P<0.05). Although the frequency of CD27-IgM+B naive subsets was similar in both groups, there was a significantly higher proportion of CD5+B cells detected in the CD27-IgM+B subsets of patients with CHC compared with HCs (P<0.05). Among CD27-IgM+B subsets, abnormal differentiation was associated with HCV infection, with significantly increased percentages of IgD+B cells and CD38+B cells in patients with CHC compared with HCs (P<0.05). In CD27+IgM+B memory subsets, the abnormality of cell differentiation was associated with a significantly increased percentage of CD38+B cells in patients with CHC compared with HCs (P<0.05). In addition, the percentage of activated CD27+IgM+B subsets in patients with CHC were significantly higher than those observed in HCs (P<0.05). The number of CD27-IgD+IgM+B, CD27-CD38+IgM+B and CD27+CD38+IgM+B cells were negatively correlated with HCV RNA in patients with CHC. These results suggest that HCV infection contributes to abnormalities in the percentage, differentiation and activation of IgM+B cell subsets and may disrupt the immune response mediated by IgM+B cells.

Effects of hepatitis C virus infection on the safety of chemotherapy for breast cancer patients.

Hepatitis C virus (HCV) is one of the major pathogens of chronic viral hepatitis, and approximately 38 million patients are infected with HCV in China. However, little information is available on the effect of HCV infection during chemotherapy for breast cancer and the impact of HCV infection on the toxicity of chemotherapy and targeted therapy. We performed a retrospective survey of 835 patients who were diagnosed with breast cancer between January 2010 and December 2015 at our institution. All patients had been screened for HCV infection at the time of breast cancer diagnosis. We retrospectively investigated the toxicities of chemotherapy and the changes in HCV load based on a review of the medical records. A total of 21 patients with positive anti-HCV antibody tests received chemotherapy. The median patient age was 46.3±11.2years. Four (19.0%) patients exhibited abnormal liver function at baseline. The morbidity of abnormal liver function at baseline was higher in HCV-infected patients (19.0% vs. 0, P=0.000). Four patients received trastuzumab therapy. Five (23.8%) patients who received chemotherapy developed hepatitis. No patients presented with HCV reactivation. The morbidity of hepatitis and the rate of disruption of chemotherapy were not significantly different between breast cancer patients without HCV infection and those with HCV infection (23.8 vs. 14.2% P=0.342, 9.5 vs. 5.0% P=0.619, respectively). HCV infection had no adverse impact on chemotherapy in breast cancer patients. However, consulting a gastroenterologist and closely monitoring liver function during the course of chemotherapy may benefit patients.

Hepatitis C virus NS3 protein enhances hepatocellular carcinoma cell invasion by promoting PPM1A ubiquitination and degradation

BackgroundGrowing evidence suggests that hepatitis C virus (HCV) contributes to hepatocellular carcinoma (HCC) by directly modulating oncogenic signaling pathways. Protein phosphatase magnesium-dependent 1A (PPM1A) has recently emerged as an important tumor suppressor as it can block a range of tumor-centric signaling pathways through protein dephosphorylation. However, the role and regulatory mechanisms of PPM1A in HCV-infected cells have not been reported.MethodsTotal, cytoplasmic, and nuclear PPM1A protein after HCV infection or overexpression of HCV nonstructural protein 3 (NS3) were detected by western blotting. The expression of PPM1A in normal liver and HCV-related HCC tissues was quantified by immunohistochemistry. The effects of HCV infection and NS3 expression on the PPM1A protein level were systematically analyzed, and the ubiquitination level of PPM1A was determined by precipitation with anti-PPM1A and immunoblotting with either anti-ubiquitin or anti-PPM1A antibody. Finally, the roles of NS3 and PPM1A in hepatoma cell migration and invasion were assessed by wound healing and transwell assays, respectively.ResultsHCV infection and replication decreased PPM1A abundance, mediated by NS3, in hepatoma cells. Compared to normal liver tissues, the expression of PPM1A was significantly decreased in the HCC tumor tissues and adjacent non-tumor tissues. NS3 directly interacted with PPM1A to promote PPM1A ubiquitination and degradation, which was dependent on its protease domain. Blockade of PPM1A through small interfering RNA significantly promoted HCC cell migration, invasion, and epithelial mesenchymal transition (EMT), which were further intensified by TGF-β1 stimulation, in vitro. Furthermore, restoration of PPM1A abrogated the NS3-mediated promotion of HCC migration and invasion to a great extent, which was dependent on its protein phosphatase function.ConclusionsOur findings demonstrate that the HCV protein NS3 can downregulate PPM1A by promoting its ubiquitination and proteasomal degradation, which might contribute to the migration and invasion of hepatoma cells and may represent a new strategy of HCV in carcinogenesis.

Hepatitis C virus infection inhibits a Src-kinase regulatory phosphatase and reduces T cell activation in vivo.

Among human RNA viruses, hepatitis C virus (HCV) is unusual in that it causes persistent infection in the majority of infected people. To establish persistence, HCV evades host innate and adaptive immune responses by multiple mechanisms. Recent studies identified virus genome-derived small RNAs (vsRNAs) in HCV-infected cells; however, their biological significance during human HCV infection is unknown. One such vsRNA arising from the hepatitis C virus (HCV) E2 coding region impairs T cell receptor (TCR) signaling by reducing expression of a Src-kinase regulatory phosphatase (PTPRE) in vitro. Since TCR signaling is a critical first step in T cell activation, differentiation, and effector function, its inhibition may contribute towards HCV persistence in vivo. The effect of HCV infection on PTPRE expression in vivo has not been examined. Here, we found that PTPRE levels were significantly reduced in liver tissue and peripheral blood mononuclear cells (PBMCs) obtained from HCV-infected humans compared to uninfected controls. Loss of PTPRE expression impaired antigen-specific TCR signaling, and curative HCV therapy restored PTPRE expression in PBMCs; restoring antigen-specific TCR signaling defects. The extent of PTPRE expression correlated with the amount of sequence complementarity between the HCV E2 vsRNA and the PTPRE 3’ UTR target sites. Transfection of a hepatocyte cell line with full-length HCV RNA or with synthetic HCV vsRNA duplexes inhibited PTPRE expression, recapitulating the in vivo observation. Together, these data demonstrate that HCV infection reduces PTPRE expression in the liver and PBMCs of infected humans, and suggest that the HCV E2 vsRNA is a novel viral factor that may contribute towards viral persistence.

Increased Mitochondrial Genetic Diversity in Persons Infected With Hepatitis C Virus.

Background & AimsThe host genetic environment contributes significantly to the outcomes of hepatitis C virus (HCV) infection and therapy response, but little is known about any effects of HCV infection on the host beyond any changes related to adaptive immune responses. HCV persistence is associated strongly with mitochondrial dysfunction, with liver mitochondrial DNA (mtDNA) genetic diversity linked to disease progression.MethodsWe evaluated the genetic diversity of 2 mtDNA genomic regions (hypervariable segments 1 and 2) obtained from sera of 116 persons using next-generation sequencing.ResultsResults were as follows: (1) the average diversity among cases with seronegative acute HCV infection was 4.2 times higher than among uninfected controls; (2) the diversity level among cases with chronic HCV infection was 96.1 times higher than among uninfected controls; and (3) the diversity was 23.1 times higher among chronic than acute cases. In 2 patients who were followed up during combined interferon and ribavirin therapy, mtDNA nucleotide diversity decreased dramatically after the completion of therapy in both patients: by 100% in patient A after 54 days and by 70.51% in patient B after 76 days.ConclusionsHCV infection strongly affects mtDNA genetic diversity. A rapid decrease in mtDNA genetic diversity observed after therapy-induced HCV clearance suggests that the effect is reversible, emphasizing dynamic genetic relationships between HCV and mitochondria. The level of mtDNA nucleotide diversity can be used to discriminate recent from past infections, which should facilitate the detection of recent transmission events and thus help identify modes of transmission.

Endoplasmic reticulum stress links hepatitis C virus RNA replication to wild-type PGC-1α/liver-specific PGC-1α upregulation

Hepatitis C virus (HCV) causes not only severe liver problems but also extrahepatic manifestations, such as insulin resistance (IR). Wild-type peroxisome proliferator-activated receptor gamma coactivator 1 alpha (WT-PGC-1α) is essential in hepatic gluconeogenesis and has recently been demonstrated to link HCV infection to hepatic insulin resistance (IR). A recent study has characterized a novel human liver-specific PGC-1α (L-PGC-1α) transcript, which is proposed to reflect human adaption to more complex pathways. However, the effect of HCV infection on L-PGC-1α expression and the mechanism by which HCV modulates WT-PGC-1α/L-PGC-1α remain unclear. In this study, we showed that HCV infection upregulated both WT-PGC-1α and L-PGC-1α, which further promoted HCV production. The upregulation of both PGC-1α isoforms depended on HCV RNA replication. By using promoter-luciferase reporters, kinase inhibitors, and dominant negative mutants, we further observed that the HCV-induced upregulation of WT-PGC-1α was mediated by the phosphorylation of cyclic AMP (cAMP)-responsive element-binding protein (CREB), whereas that of L-PGC-1α was mediated by CREB phosphorylation and forkhead box O1 dephosphorylation. Moreover, HCV infection induced endoplasmic reticulum (ER) stress, and pharmacological induction of ER stress upregulated WT-PGC-1α/L-PGC-1α and phosphorylated CREB. In contrast, pharmacological inhibition of HCV-induced ER stress impaired WT-PGC-1α/L-PGC-1α upregulation along with decreased phosphorylated CREB. The correlation of hepatic mPGC-1α with ER stress was further confirmed in mice. Overall, HCV infection upregulates both WT-PGC-1α and L-PGC-1α through an ER stress-mediated, phosphorylated CREB-dependent pathway, and both PGC-1α isoforms promote HCV production in turn. IMPORTANCE HCV causes not only severe liver problems but also extrahepatic manifestations, such as insulin resistance (IR). As a key regulator in energy metabolism, wild-type PGC-1α (WT-PGC-1α), has recently been demonstrated to link HCV infection to hepatic IR. A recent study has characterized a novel human liver-specific PGC-1α (L-PGC-1α), which reflects human adaption to more complex pathways. However, the effect of HCV infection on L-PGC-1α expression and the mechanism by which HCV regulates WT-PGC-1α/L-PGC-1α remain unclear. In this study, we showed that HCV infection upregulated both WT-PGC-1α and L-PGC-1α, which further promoted HCV production. WT-PGC-1α upregulation was mediated by CREB phosphorylation, whereas L-PGC-1α upregulation was mediated by CREB phosphorylation and FoxO1 dephosphorylation. HCV-induced ER stress mediated WT-PGC-1α/L-PGC-1α upregulation and CREB phosphorylation. Overall, this study provides new insights into the mechanism by which HCV upregulates WT-PGC-1α/L-PGC-1α and highlights the novel intervention of HCV-ER stress-PGC-1α signaling for HCV therapy and HCV-induced IR therapy.

The impact of hepatitis C virus infection on early post-liver transplantation complications and early graft function in a single low-volume liver transplant center

Background. End-stage liver disease associated with hepatitis C virus (HCV) infection has become one of the leading indications for liver transplantation. The effect of HCV infection on patients and long-term graft survival after orthotopic liver transplantation is well known. The aim of this study was to evaluate the impact of HCV infection on early post-liver transplantation complications and early graft function. Materials and methods. Between July 2005 and February 2015 60 cadaveric orthotopic liver transplantations were performed in 58 adult patients at the Vilnius University Hospital Santariškių Clinics. We retrospectively reviewed our low-volume liver transplant center experience. To evaluate the changes that occurred in HCV-positive and HCV-negative transplant recipients, the study population was divided into two groups according to their HCV status. Statistical analysis was performed using the Microsoft Excel and SPSS 20.0 program. Group differences and data reliability were determined by the Student’s t-test. Results. For 21 patients (35%) the indication for liver transplantation was end-stage liver disease due to HCV infection and for 39 patients (65%) there was another (non-HCV infection) indication. Overall, 29 patients (48%) have developed early biliary and/or vascular complications after transplantation: vascular complications were observed in 17 patients (28%) and biliary complications were observed in 12 patients (20%). Early graft function was good or fair in 52 patients (87%), primary dysfunction was observed in 8 (13%) patients. Conclusions. The incidence of early post-transplant complications and early graft dysfunction had no statistically significant difference according to the patient’s HCV status.

Impairment of type I but not type III IFN signaling by hepatitis C virus infection influences antiviral responses in primary human hepatocytes.

Peginterferon lambda-1a (Lambda), a type III interferon (IFN), acts through a unique receptor complex with limited cellular expression outside the liver which may result in a differentiated tolerability profile compared to peginterferon alfa (alfa). In Phase 2b clinical studies, Lambda administered in combination with ribavirin (RBV) was efficacious in patients with hepatitis C virus (HCV) infection representing genotypes 1 through 4, and was associated with more rapid declines in HCV RNA compared to alfa plus RBV. To gain insights into potential mechanisms for this finding, we investigated the effects of HCV replication on IFN signaling in primary human hepatocytes (PHH) and in induced hepatocyte-like cells (iHLCs). HCV infection resulted in rapid down-regulation of the type I IFN-α receptor subunit 1 (IFNAR1) transcript in hepatocytes while the transcriptional level of the unique IFN-λ receptor subunit IL28RA was transiently increased. In line with this observation, IFN signaling was selectively impaired in infected cells upon stimulation with alfa but not in response to Lambda. Importantly, in contrast to alfa, Lambda was able to induce IFN-stimulated gene (ISG) expression in HCV-infected hepatocytes, reflecting the onset of innate responses. Moreover, global transcriptome analysis in hepatocytes indicated that Lambda stimulation prolonged the expression of various ISGs that are potentially beneficial to antiviral defense mechanisms. Collectively, these observed effects of HCV infection on IFN receptor expression and signaling within infected hepatocytes provide a possible explanation for the more pronounced early virologic responses observed in patients treated with Lambda compared to alfa.

Hepatitis C Virus Attenuates Interferon-Induced Major Histocompatibility Complex Class I Expression and Decreases CD8+ T Cell Effector Functions

Major histocompatibility complex (MHC) class I-restricted CD8(+) T cells are required for clearance of hepatitis C virus (HCV) infection. MHC class I expression is up-regulated by type I and II interferons (IFNs). However, little is known about the effects of HCV infection on IFN-induced expression of MHC class I. We used the HCV cell culture system (HCVcc) with the genotype 2a Japanese fulminant hepatitis-1 strain to investigate IFN-induced expression of MHC class I and its regulatory mechanisms. HCVcc-infected Huh-7.5 cells were analyzed by flow cytometry, metabolic labeling, immunoprecipitation, and immunoblotting analyses. Protein kinase R (PKR) was knocked down with lentiviruses that express small hairpin RNAs. The functional effects of MHC class I regulation by HCV were demonstrated in co-culture studies, using HCV-specific CD8(+) T cells. Although the baseline level of MHC class I was not affected by HCV infection, IFN-induced expression of MHC class I was notably attenuated in HCV-infected cells. This was associated with replicating HCV RNA, not with viral protein. HCV infection reduced IFN-induced synthesis of MHC class I protein and induced phosphorylation of PKR and eIF2α. IFN-induced MHC class I expression was restored by small hairpin RNA-mediated knockdown of PKR in HCV-infected cells. Co-culture of HCV-specific CD8(+) T cells and HCV-infected cells that expressed HLA-A2 demonstrated that HCV infection reduced the effector functions of HCV-specific CD8(+) T cells; these functions were restored by small hairpin RNA-mediated knockdown of PKR. IFN-induced expression of MHC class I is attenuated in HCV-infected cells by activation of PKR, which reduces the effector functions of HCV-specific CD8(+) T cells. This appears to be an important mechanism by which HCV circumvents antiviral adaptive immune responses.

Genomic polymorphisms in 3β‐hydroxysterol Δ24‐reductase promoter sequences

It was recently reported by the present team that 3β-hydroxysterol Δ24-reductase (DHCR24) is induced by hepatitis C virus (HCV) infection. In addition, upregulation of DHCR24 impairs p53 activity. In human hepatoma HuH-7 cells, the degree of DHCR24 expression is higher than in normal hepatic cell lines (WRL68) at the transcriptional level. The genomic promoter sequence of DHCR24 was characterized and nucleotide substitutions were observed in HuH-7 cells at nucleotide numbers -1453 (G to A), -1420 (G to T), -488 (A to C) and -200 (G to C). The mutations of these sequences from HuH-7 cell types to WRL68 cell types suppressed DHCR24 gene promoter activity. The sequences were further characterized in hepatocytes from patient tissues. Four tissues from HCV-positive patients with cirrhosis or hepatocellular carcinoma (#1, 2, 3, 5) possessed HuH-7 cell type sequences. Interestingly, one patient with liver cirrhosis (#4) possessed WRL68 cell-type sequences; this patient had been infected with HCV and was HCV negative for 17 years after interferon therapy. Next, the effect of HCV infection on these polymorphisms was examined in humanized chimeric mouse liver and HuH-7 cells. The human hepatocytes possess WRL68 cell type and did not show the nucleotide substitution after HCV infection. The HCV-replicon was removed by interferon treatment and established the cured K4 cells. These cells possess HuH-7 cell type sequences. Thus, this study showed the genomic polymorphism in DHCR24 promoter is not directly influenced by HCV infection.

Protective Effect of CCR5-Δ32 Against HIV Infection by the Heterosexual Mode of Transmission in a Polish Population

Effects of chemokine receptor alleles (CCR5-Δ32 and CCR2-64I) on susceptibility to human immunodeficiency virus (HIV) infection were studied in a Polish population. The CCR5 and CCR2 genotypes were determined for 311 healthy, HIV-negative individuals (control group), 121 exposed to HIV infection but uninfected (EU group), and 470 HIV-positive patients. The frequency of the alleles in the control group was calculated as 0.12 for both CCR5-Δ32 and CCR2-64I. The logistic regression method was used to analyze the effects of the described factors. A protective effect was observed for the CCR5-Δ32 allele but only in the case of heterosexual exposure. Prevalence of the CCR5-Δ32/+ genotype in HIV(+) patients infected via the heterosexual route (n=61; 8.2%) was much lower than in the control group (n=311; 21.5%); in the heterosexually exposed uninfected group it was slightly higher (n=28; 25%). This suggested that in this mode of infection, the native CCR5 expression level was crucial for establishment of infection. Individuals with the CCR5-Δ32 allele have more than three times less chance of infection in the case of HIV heterosexual exposure (odds ratio, 3.37; 95% confidence interval, 1.055-10.76). However, a protective effect of the CCR5-Δ32/+ genotype was not observed in the case of intravenous drug users (IDUs). The rates of the genotype were similar in HIV-infected IDU individuals (n=356; 17.7%) and in exposed uninfected patients (n=84; 15.5%), not significantly different from control group. No effect of the CCR2 genotype was observed. The analysis revealed that the important factor increasing infection risk was, in particular, hepatitis C virus (HCV) infection (odds ratio, 12.9). Moreover, the effect of HCV infection was found to be age dependent. Susceptibility to HIV infection resulting from HCV positivity became weaker (6% per year) with increasing age.

HCV Coinfection Increases Mortality in Patients with AIDS

As HIV-infected patients live longer, hepatic disease related to hepatitis C virus (HCV) infection has become a leading cause of death. To assess the effect of HCV infection on mortality in patients with AIDS — a group that has many competing risk factors for death — investigators studied patients …

Effect of Hepatitis C Virus Infection on the Left Ventricular Systolic and Diastolic Functions

Hepatitis secondary to infection with the hepatitis C virus (HCV) is one of the most common causes of viral hepatitis worldwide. Multiple extrahepatic manifestations of HCV infection have been recognized. Dilated and hypertrophic cardiomyopathy associated with HCV infection have been recently described in the literature; however, the effect of HCV infection on the left ventricular systolic and diastolic functions is unknown. Therefore, in this study we aimed to examine left ventricular systolic and diastolic functions in HCV patients. The study included 50 anti-HCV positive patients and 50 persons for control groups. We performed transthorasic echocardiography and P-wave analysis on all participants. We compared left ventricle diastolic parameters, left ventricle ejection fraction, and P-wave dispersion (Pd) between these two groups. In the group with anti-HCV positivity, the ratio of E/A was found to be lower (1.2 ± 0.7 and 1.37 ± 0.6, P = 0.003); the ratio of E/Em was found to be higher (7.6 ± 1.51 and 6.8 ± 1.72, P = 0.0001). Maximum P-wave duration (Pmax) and Pd were higher in the patient group (99.3 ± 8 and 82.4 ± 7.8, P = 0.004; 44.1 ± 0.9 and 25.3 ± 1.5, P = 0.001). No other statistically significant difference was found between the two groups with regard to the left ventricle systolic and diastolic parameters. Our findings show that HCV infection may be associated with left ventricular systolic and diastolic dysfunction and cardiac arrhythmias.

Characterization of chronic HCV infection-induced apoptosis

BackgroundTo understand the complex and largely not well-understood apoptotic pathway and immune system evasion mechanisms in hepatitis C virus (HCV)-associated hepatocellular carcinoma (HCC) and HCV associated chronic hepatitis (CH), we studied the expression patterns of a number of pro-apoptotic and anti-apoptotic genes (Fas, FasL, Bcl-2, Bcl-xL and Bak) in HepG2 cell line harboring HCV- genotype-4 replication. For confirmation, we also assessed the expression levels of the same group of genes in clinical samples obtained from 35 HCC and 34 CH patients.MethodsViral replication was assessed in the tissue culture medium by RT-PCR, quantitative Real-Time PCR (qRT-PCR); detection of HCV core protein by western blot and inhibition of HCV replication with siRNA. The expression level of Fas, FasL, Bcl-2, Bcl-xL and Bak was assessed by immunohistochemistry and RT-PCR whereas caspases 3, 8 and 9 were assessed by colorimetric assay kits up to 135 days post infection.ResultsThere was a consistent increase in apoptotic activity for the first 4 weeks post-CV infection followed by a consistent decrease up to the end of the experiment. The concordance between the changes in the expression levels of Fas, FasL, Bcl-2, Bcl-xL and Bak in vitro and in situ was statistically significant (p < 0.05). Fas was highly expressed at early stages of infection in cell lines and in normal control liver tissues followed by a dramatic reduction post-HCV infection and an increase in the expression level of FasL post HCV infection. The effect of HCV infection on other apoptotic proteins started very early post-infection, suggesting that hepatitis C modulating apoptosis by modulating intracellular pro-apoptotic signals.ConclusionsChronic HCV infection differently modulates the apoptotic machinery during the course of infection, where the virus induces apoptosis early in the course of infection, and as the disease progresses apoptosis is modulated. This study could open a new opportunity for understanding the various signaling of apoptosis and in the developing a targeted therapy to inhibit viral persistence and HCC development.

Reduced NK cell cytotoxicity in hepatitis C infection is associated with reduced levels of cytotoxicity markers NKP30 and NKP46

IntroductionBackground: Infection with hepatitis C virus (HCV) results in life long chronic infection in the majority of subjects, indicating the virus has developed immunoevasion strategies. Treatment with interferon α (IFNα)...