|
1
|
Padilha MDM, Melo FTDV, Laurentino RV, da Silva ANMR, Feitosa RNM. Dysregulation in the microbiota by HBV and HCV infection induces an altered cytokine profile in the pathobiome of infection. Braz J Infect Dis 2025; 29:104468. [PMID: 39608222 PMCID: PMC11636304 DOI: 10.1016/j.bjid.2024.104468] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Revised: 10/07/2024] [Accepted: 11/03/2024] [Indexed: 11/30/2024] Open
Abstract
Viral hepatitis is a public health problem, about 1 million people die due to complications of this viral disease, the etiological agents responsible for inducing cirrhosis and cellular hepatocarcinoma are HBV and HCV, both hepatotropic viruses that cause asymptomatic infection in most cases. The regulation of the microbiota performs many physiological functions, which can induce normal intestinal function and produce essential nutrients for the human body. Metabolites derived from gut microbiota or direct regulation of host immunity and metabolism have been reported to profoundly affect tumorigenesis in liver disease. If the microbiota is unbalanced, both exogenous and symbiotic microorganisms can affect a pathological process. It is well understood that the microbiota plays a role in viral diseases and infections, specifically the hepatic portal pathway has been linked to the gut-liver axis. In HBV and HCV infections, the altered bacterial representatives undergo a state of dysbiosis, with subsequent establishment of the pathobiome with overexpression of taxons such as Bacteroides, Clostridium, Lactobacillus, Enterobacter, and Enterococcus. This dysregulated microbiome induces a microenvironment conducive to the development of hepatic complications in patients with acute and chronic HBV and HCV infection, with subsequent dysregulation of cytokines IFN-α/β, TNF-α, IL-1β, TGF-β, IL-6 and IL-10, which alter the dysfunction and damage of the hepatic portal system. In view of the above, this review aimed to correlate the pathophysiological mechanisms in HBV and HCV infection, the dysregulation of the microbiome in patients infected with HBV and HCV, the most altered cytokines in the microbiome, and the most altered bacterial representatives in the pathobiome of infection.
Collapse
Affiliation(s)
- Marcos Daniel Mendes Padilha
- Universidade Federal do Pará (UFPA), Instituto de Ciências Biológicas, Laboratório de Virologia, Belém, PA, Brazil.
| | | | - Rogério Valois Laurentino
- Universidade Federal do Pará (UFPA), Instituto de Ciências da Saúde, Health Sciences, Belém, PA, Brazil
| | | | | |
Collapse
|
|
2
|
Lee J, Gil D, Park H, Lee Y, Mun SJ, Shin Y, Jo E, Windisch MP, Kim JH, Son MJ. A multicellular liver organoid model for investigating hepatitis C virus infection and nonalcoholic fatty liver disease progression. Hepatology 2024; 80:186-201. [PMID: 37976400 DOI: 10.1097/hep.0000000000000683] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Accepted: 10/26/2023] [Indexed: 11/19/2023]
Abstract
BACKGROUND AND AIMS HCV infection can be successfully managed with antiviral therapies; however, progression to chronic liver disease states, including NAFLD, is common. There is currently no reliable in vitro model for investigating host-viral interactions underlying the link between HCV and NAFLD; although liver organoids (LOs) show promise, they currently lack nonparenchymal cells, which are key to modeling disease progression. APPROACH AND RESULTS Here, we present a novel, multicellular LO model using a coculture system of macrophages and LOs differentiated from the same human pluripotent stem cells (PSCs). The cocultured macrophages shifted toward a Kupffer-like cell type, the liver-resident macrophages present in vivo , providing a suitable model for investigating NAFLD pathogenesis. With this multicellular Kupffer-like cell-containing LO model, we found that HCV infection led to lipid accumulation in LOs by upregulating host lipogenesis, which was more marked with macrophage coculture. Reciprocally, long-term treatment of LOs with fatty acids upregulated HCV amplification and promoted inflammation and fibrosis. Notably, in our Kupffer-like cell-containing LO model, the effects of 3 drugs for NASH that have reached phase 3 clinical trials exhibited consistent results with the clinical outcomes. CONCLUSIONS Taken together, we introduced a multicellular LO model consisting of hepatocytes, Kupffer-like cells, and HSCs, which recapitulated host-virus intercommunication and intercellular interactions. With this novel model, we present a physiologically relevant system for the investigation of NAFLD progression in patients with HCV.
Collapse
Affiliation(s)
- Jaeseo Lee
- Stem Cell Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
| | - Dayeon Gil
- Korea National Stem Cell Bank, Chungcheongbuk-do, Republic of Korea
- Department of Chronic Diseases Convergence Research, Division of Intractable Diseases Research, Korea National Institute of Health, Osong Health Technology Administration Complex, Republic of Korea
| | - Hyeyeon Park
- Korea National Stem Cell Bank, Chungcheongbuk-do, Republic of Korea
- Department of Chronic Diseases Convergence Research, Division of Intractable Diseases Research, Korea National Institute of Health, Osong Health Technology Administration Complex, Republic of Korea
| | - Youngsun Lee
- Korea National Stem Cell Bank, Chungcheongbuk-do, Republic of Korea
- Department of Chronic Diseases Convergence Research, Division of Intractable Diseases Research, Korea National Institute of Health, Osong Health Technology Administration Complex, Republic of Korea
| | - Seon Ju Mun
- Stem Cell Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
| | - Yongbo Shin
- Stem Cell Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
- Department of Functional Genomics, Korea University of Science & Technology (UST), Daejeon, Republic of Korea
| | - Eunji Jo
- Applied Molecular Virology Laboratory, Institute Pasteur Korea, Seongnam-si, Republic of Korea
| | - Marc P Windisch
- Applied Molecular Virology Laboratory, Institute Pasteur Korea, Seongnam-si, Republic of Korea
| | - Jung-Hyun Kim
- Korea National Stem Cell Bank, Chungcheongbuk-do, Republic of Korea
- Department of Chronic Diseases Convergence Research, Division of Intractable Diseases Research, Korea National Institute of Health, Osong Health Technology Administration Complex, Republic of Korea
- College of Pharmacy, Ajou University, Suwon, Republic of Korea
| | - Myung Jin Son
- Stem Cell Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
- Department of Functional Genomics, Korea University of Science & Technology (UST), Daejeon, Republic of Korea
- School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea
| |
Collapse
|
|
3
|
Woo J, Choi Y. Biomarkers in Detection of Hepatitis C Virus Infection. Pathogens 2024; 13:331. [PMID: 38668286 PMCID: PMC11054098 DOI: 10.3390/pathogens13040331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Revised: 04/10/2024] [Accepted: 04/12/2024] [Indexed: 04/29/2024] Open
Abstract
The hepatitis C virus (HCV) infection affects 58 million people worldwide. In the United States, the incidence rate of acute hepatitis C has doubled since 2014; during 2021, this increased to 5% from 2020. Acute hepatitis C is defined by any symptom of acute viral hepatitis plus either jaundice or elevated serum alanine aminotransferase (ALT) activity with the detection of HCV RNA, the anti-HCV antibody, or hepatitis C virus antigen(s). However, most patients with acute infection are asymptomatic. In addition, ALT activity and HCV RNA levels can fluctuate, and a delayed detection of the anti-HCV antibody can occur among some immunocompromised persons with HCV infection. The detection of specific biomarkers can be of great value in the early detection of HCV infection at an asymptomatic stage. The high rate of HCV replication (which is approximately 1010 to 1012 virions per day) and the lack of proofreading by the viral RNA polymerase leads to enormous genetic diversity, creating a major challenge for the host immune response. This broad genetic diversity contributes to the likelihood of developing chronic infection, thus leading to the development of cirrhosis and liver cancer. Direct-acting antiviral (DAA) therapies for HCV infection are highly effective with a cure rate of up to 99%. At the same time, many patients with HCV infection are unaware of their infection status because of the mostly asymptomatic nature of hepatitis C, so they remain undiagnosed until the liver damage has advanced. Molecular mechanisms induced by HCV have been intensely investigated to find biomarkers for diagnosing the acute and chronic phases of the infection. However, there are no clinically verified biomarkers for patients with hepatitis C. In this review, we discuss the biomarkers that can differentiate acute from chronic hepatitis C, and we summarize the current state of the literature on the useful biomarkers that are detectable during acute and chronic HCV infection, liver fibrosis/cirrhosis, and hepatocellular carcinoma (HCC).
Collapse
Affiliation(s)
| | - Youkyung Choi
- Division of Viral Hepatitis, National Center for HIV, Viral Hepatitis, STD and TB Prevention, US Centers for Disease Control and Prevention (CDC), Atlanta, GA 30329-4018, USA;
| |
Collapse
|
|
4
|
Chapin-Bardales J, Asher A, Broz D, Teshale E, Mixson-Hayden T, Poe A, Handanagic S, Blanco C, Wejnert C. Hepatitis C virus infection and co-infection with HIV among persons who inject drugs in 10 U.S. cities-National HIV Behavioral Surveillance, 2018. THE INTERNATIONAL JOURNAL OF DRUG POLICY 2024:104387. [PMID: 38531730 DOI: 10.1016/j.drugpo.2024.104387] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Revised: 02/13/2024] [Accepted: 03/06/2024] [Indexed: 03/28/2024]
Abstract
BACKGROUND Characterizing acute and chronic hepatitis C virus (HCV) infection and HIV/HCV co-infection among persons who inject drugs (PWID) can inform elimination efforts. METHODS During 2018 National HIV Behavioral Surveillance in 10 U.S. metropolitan statistical areas (MSAs), PWID were recruited using respondent-driven sampling and offered a survey, HIV testing, and HCV antibody and RNA testing. We examined prevalence and associated characteristics of HCV infection and HIV/HCV co-infection. Associations were assessed using log-linked Poisson regression models with robust standard errors accounting for clustering by recruitment chain and adjusting for MSA and network size. RESULTS Overall, 44.2% had current HCV infection (RNA detected), with 3.9% classified as acute infection (HCV antibody non-reactive/RNA detected) and 40.3% as chronic (HCV antibody reactive/RNA detected). Four percent had HIV/HCV co-infection. Current HCV infection was significantly higher among PWID who were male, White, injected >1 time/day, shared syringes in past year, and shared injection equipment in past year. PWID who were transgender, injecting >5 years, and most often injected speedball (heroin and cocaine together) or stimulants alone were more likely to have HIV/HCV co-infection. Among PWID who never previously had HCV infection, 9.9% had acute HCV infection. Among PWID who started injecting ≤5 years ago, 41.5% had already acquired HCV infection. CONCLUSIONS Acute and chronic HCV infections were substantial among a sample of PWID in 10 U.S. MSAs. Accessibility to HCV RNA testing, promoting safer practices, and intervening early with harm reduction programs for recent injection initiates will be critical to disease elimination efforts for PWID.
Collapse
Affiliation(s)
| | - Alice Asher
- Division of Viral Hepatitis, Centers for Disease Control and Prevention, Atlanta, GA, USA
| | - Dita Broz
- Division of HIV Prevention, Centers for Disease Control and Prevention, Atlanta, GA, USA
| | - Eyasu Teshale
- Division of Viral Hepatitis, Centers for Disease Control and Prevention, Atlanta, GA, USA
| | - Tonya Mixson-Hayden
- Division of Viral Hepatitis, Centers for Disease Control and Prevention, Atlanta, GA, USA
| | - Amanda Poe
- Division of Viral Hepatitis, Centers for Disease Control and Prevention, Atlanta, GA, USA
| | - Senad Handanagic
- Division of HIV Prevention, Centers for Disease Control and Prevention, Atlanta, GA, USA
| | - Carlos Blanco
- Division of Epidemiology, Services, and Prevention Research, National Institute on Drug Abuse, Bethesda, MD, USA
| | - Cyprian Wejnert
- Division of HIV Prevention, Centers for Disease Control and Prevention, Atlanta, GA, USA
| |
Collapse
|
|
5
|
Poddar S, Roy R, Kar P. The conformational dynamics of Hepatitis C Virus E2 glycoprotein with the increasing number of N-glycosylation unraveled by molecular dynamics simulations. J Biomol Struct Dyn 2024:1-16. [PMID: 38393644 DOI: 10.1080/07391102.2024.2319679] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2023] [Accepted: 02/12/2024] [Indexed: 02/25/2024]
Abstract
The Hepatitis C Virus (HCV), responsible for causing hepatitis and a significant contributor to liver disorders, presents a challenge for treatment due to its high genetic variability. Despite efforts, there is still no effective medication available for this virus. One of the promising targets for drug development involves targeting glycoprotein E2. However, our understanding of the dynamic behavior of E2 and its associated glycans remains limited. In this study, we investigated the dynamic characteristics of E2 with varying degrees of glycosylation using all-atom molecular dynamics simulations. We also explored glycan's interactions with the protein and among themselves. An overall increase in correlation between the vital protein regions was observed with an increase in glycan number. The protein dynamics is followed by the analysis of glycan dynamics, where the flexibility of the individual glycans was analyzed in their free and bound state, which revealed a decrease in their fluctuation in some cases. Furthermore, we generated the free energy landscape of individual N-glycan linkages in both free and bound states and observed both increases and decreases in flexibility, which can be attributed to the formation and breakage of hydrogen bonds with amino acids. Finally, we found that for a high glycosylation system, glycans interact with glycoprotein and form hydrogen bonds among themselves. Moreover, the hydrogen bond profiles of a given glycan can vary when influenced by other glycans. In summary, our study provides valuable insights into the dynamics of the core region of HCV E2 glycoprotein and its associated glycans.
Collapse
Affiliation(s)
- Sayan Poddar
- Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Indore, Madhya Pradesh, India
| | - Rajarshi Roy
- Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Indore, Madhya Pradesh, India
| | - Parimal Kar
- Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Indore, Madhya Pradesh, India
| |
Collapse
|
|
6
|
Kumari S, Kessel A, Singhal D, Kaur G, Bern D, Lemay-St-Denis C, Singh J, Jain S. Computational identification of a multi-peptide vaccine candidate in E2 glycoprotein against diverse Hepatitis C virus genotypes. J Biomol Struct Dyn 2023; 41:11044-11061. [PMID: 37194293 DOI: 10.1080/07391102.2023.2212777] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Accepted: 12/11/2022] [Indexed: 05/18/2023]
Abstract
Hepatitis C Virus (HCV) is estimated to affect nearly 180 million people worldwide, culminating in ∼0.7 million yearly casualties. However, a safe vaccine against HCV is not yet available. This study endeavored to identify a multi-genotypic, multi-epitopic, safe, and globally competent HCV vaccine candidate. We employed a consensus epitope prediction strategy to identify multi-epitopic peptides in all known envelope glycoprotein (E2) sequences, belonging to diverse HCV genotypes. The obtained peptides were screened for toxicity, allergenicity, autoimmunity and antigenicity, resulting in two favorable peptides viz., P2 (VYCFTPSPVVVG) and P3 (YRLWHYPCTV). Evolutionary conservation analysis indicated that P2 and P3 are highly conserved, supporting their use as part of a designed multi-genotypic vaccine. Population coverage analysis revealed that P2 and P3 are likely to be presented by >89% Human Leukocyte Antigen (HLA) molecules from six geographical regions. Indeed, molecular docking predicted the physical binding of P2 and P3 to various representative HLAs. We designed a vaccine construct using these peptides and assessed its binding to toll-like receptor 4 (TLR-4) by molecular docking and simulation. Subsequent analysis by energy-based and machine learning tools predicted high binding affinity and pinpointed the key binding residues (i.e. hotspots) in P2 and P3. Also, a favorable immunogenic profile of the construct was predicted by immune simulations. We encourage the scientific community to validate our vaccine construct in vitro and in vivo.Communicated by Ramaswamy H. Sarma.
Collapse
Affiliation(s)
- Shweta Kumari
- University Institute of Biotechnology, Chandigarh University, Mohali, Punjab, India
| | - Amit Kessel
- Department of Biochemistry and Molecular Biology, Faculty of Life Sciences, Tel-Aviv University, Tel-Aviv, Israel
| | - Divya Singhal
- University Institute of Biotechnology, Chandigarh University, Mohali, Punjab, India
| | - Gurpreet Kaur
- Department of Biotechnology, Thapar Institute of Engineering and Technology, Patiala, Punjab, India
| | - David Bern
- Department of Biochemistry and Molecular Biology, Faculty of Life Sciences, Tel-Aviv University, Tel-Aviv, Israel
| | - Claudèle Lemay-St-Denis
- Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, QC, Canada
- PROTEO, The Québec Network for Research on Protein, Function, Engineering and Applications, Québec, QC, Canada
- CGCC, Center in Green Chemistry and Catalysis, Montréal, QC, Canada
| | - Jasdeep Singh
- University Institute of Biotechnology, Chandigarh University, Mohali, Punjab, India
| | - Sahil Jain
- University Institute of Biotechnology, Chandigarh University, Mohali, Punjab, India
- Department of Biochemistry and Molecular Biology, Faculty of Life Sciences, Tel-Aviv University, Tel-Aviv, Israel
| |
Collapse
|
|
7
|
Sabei FY, Y Safhi A, Almoshari Y, Salawi A, H Sultan M, Ali Bakkari M, Alsalhi A, A Madkhali O, M Jali A, Ahsan W. Structure-based virtual screening of natural compounds as inhibitors of HCV using molecular docking and molecular dynamics simulation studies. J Biomol Struct Dyn 2023; 42:11574-11585. [PMID: 37776007 DOI: 10.1080/07391102.2023.2263588] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Accepted: 08/28/2023] [Indexed: 10/01/2023]
Abstract
The hepatitis C virus (HCV), which causes hepatitis C, is a viral infection that damages the liver and causes inflammation in the liver. New potentially effective antiviral drugs are required for its treatment owing to various issues associated with the existing medications, including moderate to severe adverse effects, higher costs, and the emergence of drug-resistant strains. The objective of the current study was to utilize computational techniques to assess the anti-HCV efficacy of certain phytochemicals against tetraspanin (CD81) and claudin 1 (CLDN1) entry proteins. A 200-nanosecond molecular dynamics (MD) simulation was employed to examine the stability of the lead-protein complexes. Free binding energy and molecular docking calculations were conducted utilizing MM/GBSA method, and the selectivity of hit compounds for CD81 and CLDN1 was determined. Five significant CD81 and CLDN1 inhibitors were identified: Petasiphenone, Silibinin, Tanshinone IIA, Taxifolin, and Topaquinone. The MM/GBSA analysis of the compounds revealed high free binding energies. All the identified compounds were stable within the CD81 and CLDN1 binding pockets. This study indicated the promising inhibitory potential of the identified compounds against CD81 and CLDN1 receptors and might develop into potential viral entry inhibitors. However, to validate the chemotherapeutic capabilities of the discovered leads extensive preclinical research is required.Communicated by Ramaswamy H. Sarma.
Collapse
Affiliation(s)
- Fahad Y Sabei
- Department of Pharmaceutics, College of Pharmacy, Jazan University, Jazan, Saudi Arabia
| | - Awaji Y Safhi
- Department of Pharmaceutics, College of Pharmacy, Jazan University, Jazan, Saudi Arabia
| | - Yosif Almoshari
- Department of Pharmaceutics, College of Pharmacy, Jazan University, Jazan, Saudi Arabia
| | - Ahmad Salawi
- Department of Pharmaceutics, College of Pharmacy, Jazan University, Jazan, Saudi Arabia
| | - Muhammad H Sultan
- Department of Pharmaceutics, College of Pharmacy, Jazan University, Jazan, Saudi Arabia
| | - Mohammed Ali Bakkari
- Department of Pharmaceutics, College of Pharmacy, Jazan University, Jazan, Saudi Arabia
| | - Abdullah Alsalhi
- Department of Pharmaceutics, College of Pharmacy, Jazan University, Jazan, Saudi Arabia
| | - Osama A Madkhali
- Department of Pharmaceutics, College of Pharmacy, Jazan University, Jazan, Saudi Arabia
| | - Abdulmajeed M Jali
- Department of Pharmacology and Toxicology, College of Pharmacy, Jazan University, Jazan, Saudi Arabia
| | - Waquar Ahsan
- Department of Pharmaceutical Chemistry and Pharmacognosy, College of Pharmacy, Jazan University, Jazan, Saudi Arabia
| |
Collapse
|
|
8
|
Rosenberg J, Sola O, Visconti A. Approach to Elevated Liver Enzymes. Prim Care 2023; 50:363-376. [PMID: 37516508 DOI: 10.1016/j.pop.2023.03.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/31/2023]
Abstract
Abnormal liver tests are one of the most common challenges in the primary care setting. Primary care practitioners order these tests for numerous reasons, including investigating abdominal signs and symptoms or suspected alcohol-use disorder, or to determine medication adverse effects. Evaluation should be guided by both the clinical presentation and the pattern of injury. In this article, we will focus on the epidemiology, pathophysiology, clinical presentation, diagnostic work-up, and management of elevated liver enzymes, with an emphasis on the most common causes of abnormal liver testing.
Collapse
Affiliation(s)
- Jessica Rosenberg
- Department of Gastroenterology, MedStar Georgetown University Hospital, 3800 Reservoir Road Northwest, Washington, DC 20007, USA.
| | | | - Adam Visconti
- Department of Family Medicine, MedStar Georgetown University, 3800 Reservoir Road Northwest, Washington, DC 20007, USA
| |
Collapse
|
|
9
|
Zhang C, Lu J, Zhang Y, He P, Xia J, Huang M. Prevalence, diagnosis, treatment, and associated factors of hepatitis C in the United States from 1999 to 2018: A population-based cross-sectional study. LIVER RESEARCH 2022; 6:284-288. [PMID: 39957907 PMCID: PMC11791864 DOI: 10.1016/j.livres.2022.12.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/25/2021] [Revised: 06/12/2022] [Accepted: 12/06/2022] [Indexed: 12/14/2022]
Abstract
Background and aim Hepatitis C virus (HCV) infection is one of the major global health challenges, leading to a significant increase in rates of hepatic fibrosis, cirrhosis and hepatocellular carcinoma. A comprehensive nationwide survey of trends in prevalence and associated factors could facilitate preventive behavioral interventions. Herein, we sought to determine prevalence, diagnosis, treatment, and risk factors for HCV infection in the general United States (US) population. Methods This was a secondary analysis of the publicly available data from the US National Health and Nutrition Examination Survey (NHANES). The prevalence of HCV-RNA-positive (HCV-RNA+) was weighted using patient serum sample data collected from 1999 to 2018. A propensity score matching model was used due to the imbalance in the number of HCV-RNA+ and HCV-RNA-negative (HCV-RNA-) patients. Matched variables included gender, age, educational level, marital status, language, household size, alcohol consumption, smoking, number of family members and family income to poverty ratio. Results The weighted prevalence of HCV-RNA+ was 1.11% (95% confidence interval (CI): 1.02-1.20), 1.58% (95% CI: 1.42-1.74) for men and 0.67% (95% CI: 0.57-0.77) for women aged 20 years or older in the US from 1999 to 2018. The weighted prevalence of HCV-RNA+ increased from 0.87% (95% CI: 0.62-1.12) in 2013-2014, 0.95% (95% CI: 0.68-1.22) in 2015-2016 to 1.00% (95% CI: 0.72-1.28) in 2017-2018, respectively. In propensity-matched analysis, patients with HCV-RNA+ were more likely to be non-Hispanic black, and have had drug use and blood transfusions. Meanwhile, the weighted diagnostic and treatment rates were 56.27% (95% CI: 50.90-61.64) and 35.40% (95% CI: 27.64-43.16) from 1999 to 2018, respectively. Conclusions Active HCV infection rate increased between 2013 and 2018, varied by demographic and risk variables. In the direct-acting antiviral era, affordable treatment and universal screening have the potential to improve overall national health.
Collapse
Affiliation(s)
- Congnan Zhang
- Department of Infectious Diseases, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, China
| | - Jiahui Lu
- Intensive Care Unit, Jiangmen Central Hospital, Jiangmen, Guangdong, China
| | - Yajing Zhang
- Sino-French Institute of Nuclear Engineering and Technology, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Pengyuan He
- Department of Infectious Diseases, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, China
| | - Jinyu Xia
- Department of Infectious Diseases, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, China
| | - Mingxing Huang
- Office of the Dean, The Third People's Hospital of Zhuhai, Zhuhai, Guangdong, China
| |
Collapse
|
|
10
|
KARABULUT S. The Relationship Between Anti-HCV Screening and Clinical Features of Inpatients in Addiction Center. Noro Psikiyatr Ars 2022; 59:232-236. [PMID: 36160080 PMCID: PMC9466642 DOI: 10.29399/npa.27965] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Accepted: 11/12/2021] [Indexed: 06/16/2023] Open
Abstract
INTRODUCTION In this study, it was aimed to screen inpatients in the Antalya Ataturk State Hospital Alcohol and Substance Addiction Treatment Center (AMATEM) Clinic in terms of anti-hepatitis C virus (anti-HCV) seropositivity and to compare them in terms of sociodemographic data and clinical characteristics. METHOD The files of inpatients in the AMATEM Clinic of Ataturk State Hospital between July 2020 - February 2021 were retrospectively scanned and recorded with a semi-structured data form. The collected data was analysed using the SPSS 26.0 program. Independent sample t-test was used for normally distributed numerical variables, Mann-Whitney U test was used for non-normally distributed numerical variables, and chi-square test was used for categorical variables. To examine the relationship between variables showing significant difference and Anti-HCV positivity, binary logistic regression analysis was used. The limit of statistical significance was accepted as p<0.05 for all analyses. RESULTS Of the 155 patients included in the study, 57.4% were diagnosed with opiate use disorder, 40% with multiple substance use disorder. The rate of multiple substance use, syringe use, syringe sharing, self-mutilation and tattoo/piercing were significantly higher in anti-HCV positive patients (p=0.02, p<0.001, p<0.001, p=0.02, p=0.03 respectively). Patients who were positive for anti-HCV had been using substances for a longer time and were hospitalized more frequently, and the Addiction Profile Index substance abuse subscale scores were higher (p<0.001, p=0.001, p=0.01, respectively). CONCLUSION The risk of exposure to HCV in patients with substance use disorder is significantly higher than non-substance user population. It is important to perform anti-HCV screening, especially for people who inject drugs to prevent under-diagnosis of the disease. Considering the risk posed by the use and sharing of syringes, it seems necessary to develop preventive and therapeutic approaches meticulously.
Collapse
Affiliation(s)
- Sercan KARABULUT
- Antalya Atatürk State Hospital, Clinic of AMATEM, Antalya, Turkey
| |
Collapse
|
|
11
|
Khan A, Nawaz M, Ullah S, Rehman IU, Khan A, Saleem S, Zaman N, Shinwari ZK, Ali M, Wei DQ. Core amino acid substitutions in HCV-3a isolates from Pakistan and opportunities for multi-epitopic vaccines. J Biomol Struct Dyn 2022; 40:3753-3768. [PMID: 33246391 DOI: 10.1080/07391102.2020.1850353] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Hepatitis C virus (HCV), which infected 71 million worldwide and about 5%-6% are from Pakistan, is an ssRNA virus, responsible for end-stage liver disease. To date, no effective therapy is available to cure this disease. Hence, it is important to study the most prevalent genotypes infecting human population and design novel vaccine or small molecule inhibitors to control the infections associated with HCV. Therefore, in this study clinical samples (n = 35; HCV-3a) from HCV patients were subjected to Sanger sequencing method. The sequencing of the core gene, which is generally considered as conserved, involved in the detection, quantitation and genotyping of HCV was performed. Multiple mutations, that is, R46C, R70Q, L91C, G60E, N/S105A, P108A, N110I, S116V, G90S, A77G and G145R that could be linked with response to antiviral therapies were detected. Phylogenetic analysis suggests emerging viral isolates are circulating in Pakistan. Using ab initio modelling technique, we predicted the 3D structure of core protein and subjected to molecular dynamics simulation to extract the most stable conformation of the structure for further analysis. Immunoinformatic approaches were used to propose a multi-epitopes vaccine against HCV by using core protein. The vaccine constructs consist of nine CTL and three HTL epitopes joined by different linkers were docked against the two reported Toll-like receptors (TLR-3 and TLR-8). Docking of vaccine construct with TLR-3 and TLR-8 shows proper binding and in silico expression of the vaccine resulted in a CAI value of 0.93. These analyses suggest that specific immune responses may be produced by the proposed vaccine.Communicated by Ramaswamy H. Sarma.
Collapse
Affiliation(s)
- Ayyaz Khan
- Department of Biotechnology, Quaid-i-Azam University Islamabad, Islamabad, Pakistan
| | - Mehboob Nawaz
- Department of Biotechnology, Quaid-i-Azam University Islamabad, Islamabad, Pakistan
| | - Saeed Ullah
- Saidu Group of Teaching Hospital, Swat, Pakistan
| | - Irshad Ur Rehman
- Center of Biotechnology and Microbiology, University of Peshawar, Peshawar, Pakistan
| | - Abbas Khan
- Department of Bioinformatics and Biological Statistics, School of Life Sciences and Biotechnology, Shanghai Jiaotong University, Shanghai, China
| | - Shoaib Saleem
- National Center for Bioinformatics, Quaid-i-Azam University Islamabad, Islamabad, Pakistan
| | - Nasib Zaman
- Center of Biotechnology and Microbiology, University of Swat, Swat, Pakistan
| | - Zabta Khan Shinwari
- Department of Biotechnology, Quaid-i-Azam University Islamabad, Islamabad, Pakistan.,Pakistan Academy of Sciences, Islamabad, Pakistan
| | - Muhammad Ali
- Department of Biotechnology, Quaid-i-Azam University Islamabad, Islamabad, Pakistan
| | - Dong-Qing Wei
- Department of Bioinformatics and Biological Statistics, School of Life Sciences and Biotechnology, Shanghai Jiaotong University, Shanghai, China.,State Key Laboratory of Microbial Metabolism, Shanghai-Islamabad-Belgrade Joint Innovation Center on Antibacterial Resistances, Joint Laboratory of International Cooperation in Metabolic and Developmental Sciences, Ministry of Education and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, P.R. China.,Peng Cheng Laboratory, Shenzhen, Guangdong, P.R China
| |
Collapse
|
|
12
|
Butaru AE, Gheonea DI, Rogoveanu I, Diculescu M, Boicea AR, Bunescu M, Streba CT, Oancea CN. Micro-Elimination: Updated Pathway to Global Elimination of Hepatitis C in Small Communities and Industrial Settings during the COVID 19 Pandemic. J Clin Med 2021; 10:4976. [PMID: 34768496 PMCID: PMC8584569 DOI: 10.3390/jcm10214976] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 10/19/2021] [Accepted: 10/24/2021] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND In response to the goal of the World Health Organisation to eliminate hepatitis C virus infections by 2030, Romania is striving for national elimination. An already successful micro-elimination project was expanded to test-and-treat specific populations and at-risk groups. The aim of this project was to identify the individuals with HCV infection in disadvantaged regions who do not have proper medical care access. MATERIALS AND METHODS Our two-arm interventional cross-sectional study used rapid anti-HCV antibody testing on two population groups from the Romanian southwestern region of Oltenia, approached between September 2020 and May 2021. The first group consisted of predominantly over 40 years old individuals, recruited through five family doctors from two medium-sized towns (community lot-CL). We approached a second group, aged 18-65, through 11 medical offices of five large factories in the same region (industry lot, IL). A 12-items questionnaire was given to each participant, to determine risk factors and record demographic data. Eligible patients initiated antiviral therapy using direct-acting antivirals (DAAs). RESULTS We enrolled 15,383 individuals between all 16 locations. The overall prevalence by antibody testing was 0.77% (119 cases). Of these, 57 subsequently received treatment with DAAs. We identified blood transfusions as a risk factor within the CL. Participants in the IL reported a relatively high risk for the following situations: sharing of personal hygiene belongings with another person, performing previous blood transfusions, dental interventions and previous surgery. CONCLUSIONS In this global context, the use of micro-elimination allows interventions to be faster and more efficient. This is possible by targeting smaller and specific HCV risk groups.
Collapse
Affiliation(s)
- Anca Elena Butaru
- Department of Infectious Disease, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania;
| | - Dan Ionuț Gheonea
- Department of Gastroenterology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania; (D.I.G.); (I.R.)
| | - Ion Rogoveanu
- Department of Gastroenterology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania; (D.I.G.); (I.R.)
| | - Mircea Diculescu
- Department of Gastroenterology, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania;
| | - Ancuța-Ramona Boicea
- Department of Labor Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania; (A.-R.B.); (M.B.)
| | - Marius Bunescu
- Department of Labor Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania; (A.-R.B.); (M.B.)
| | - Costin-Teodor Streba
- Research Center of Gastroenterology and Hepatology of Craiova, 200638 Craiova, Romania
- Department of Pulmonology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Carmen Nicoleta Oancea
- Department of Analytical Chemistry, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania;
| |
Collapse
|
|
13
|
HCV Infection and Chronic Renal Disease. SERBIAN JOURNAL OF EXPERIMENTAL AND CLINICAL RESEARCH 2021. [DOI: 10.2478/sjecr-2021-0010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Abstract
Chronic Hepatitis C virus (HCV) infection is defined as persistence of HCV RNA in the blood for more than six months. HCV is a major cause of chronic liver disease and cirrhosis. It’s serious public health problem, affects about 71 million people worldwide. HCV doesn’t destroy hepatocytes directly. It activates the host's innate and acquired immune system and causes liver injury indirectly. Behind hepatic, HCV can cause extra-hepatic manifestations. One of them is renal disease which can lead to end-stage renal disease, ESRD. The prevalence of HCV infection in patients on hemodialysis is high, ranging from 5% to 60%. HCV infection is a significant cause of morbidity and mortality in patients with ESRD on hemodialysis. In this review, we discuss HCV infection and chronic renal disease as comorbidities, their severity and outcome.
Collapse
|
|
14
|
Ejtehadi F, Farahvashi P, Shamsaeefar A, Niknam R, Sivandzadeh GR, Aminlari L, Motazedian N, Kazemi K, Nikoupour H, Nikeghbalian S, Eghlimi H, Taghavi A, Fattahi M, Bagheri Lankarani K, Malek-Hosseini SA. Clinical Course and Outcome of Liver Transplantation in Patients with Hepatitis C in Iran. HEPATITIS MONTHLY 2021; 21. [DOI: 10.5812/hepatmon.108405] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
Abstract
Background: Hepatitis C is one of the most common causes of end-stage liver disease and liver transplant worldwide. In recent years, with the rapid advances in the treatment of hepatitis C by direct-acting antiviral drugs (DAAs), the clinical course of the disease as well as liver transplantation have had significant improvement. Also, DAAs have completely replaced interferon-based regimens in the treatment and prevention of HCV recurrence after liver transplant. Objectives: This is the first study that aimed to investigate the clinical course of liver transplantation in patients with hepatitis C in Iran. Methods: This retrospective study was conducted on patients with HCV liver transplantation within five years (2012 - 2017) with the age range of 18 to 65 years at Shiraz Organ Transplant Center. All demographic and clinical data were recorded. Pre-transplant viral load, disease recurrence, graft rejection, and mortality rate were the most important indices in this study. Results: Among 55 transplant patients, 49% had received hepatitis C treatment before liver transplantation and interferon-based regimens were more prevalent. Besides, HCV genotype 3, followed by genotype 1, was the most prevalent one. A liver biopsy was performed in patients with elevated liver enzyme levels. The numbers of patients with HCV recurrence at 2, 6, 12, and 24-month intervals were three, two, zero, and two patients, respectively. At these time intervals, eight, eight, one, and three cases of acute graft rejection were found, respectively. Eight patients died with a one-year survival rate of 85%. Sepsis and infectious complications were the most leading causes of death. Conclusions: This study is the first study of liver transplant patients with hepatitis C in Iran. In the five-year study period, rapid development was made in the treatment of HCV patients. It led to the introduction of DAAs, which replaced interferon-based therapies. The results of this study indicated the high success rate of liver transplantation in patients with hepatitis C in Iran. The results of this study could be used to compare the efficacy of DAAs in future research.
Collapse
|
|
15
|
Malikova AZ, Shcherbakova AS, Konduktorov KA, Zemskaya AS, Dalina AA, Popenko VI, Leonova OG, Morozov AV, Kurochkin NN, Smirnova OA, Kochetkov SN, Kozlov MV. Pre-Senescence Induction in Hepatoma Cells Favors Hepatitis C Virus Replication and Can Be Used in Exploring Antiviral Potential of Histone Deacetylase Inhibitors. Int J Mol Sci 2021; 22:4559. [PMID: 33925399 PMCID: PMC8123837 DOI: 10.3390/ijms22094559] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Revised: 04/16/2021] [Accepted: 04/22/2021] [Indexed: 12/22/2022] Open
Abstract
Recent evidence suggests that fibrotic liver injury in patients with chronic hepatitis C correlates with cellular senescence in damaged liver tissue. However, it is still unclear how senescence can affect replication of the hepatitis C virus (HCV). In this work, we report that an inhibitor of cyclin-dependent kinases 4/6, palbociclib, not only induced in hepatoma cells a pre-senescent cellular phenotype, including G1 arrest in the cell cycle, but also accelerated viral replicon multiplication. Importantly, suppression of HCV replication by direct acting antivirals (DAAs) was barely affected by pre-senescence induction, and vice versa, the antiviral activities of host-targeting agents (HTAs), such as inhibitors of human histone deacetylases (HDACi), produced a wide range of reactions-from a dramatic reduction to a noticeable increase. It is very likely that under conditions of the G1 arrest in the cell cycle, HDACi exhibit their actual antiviral potency, since their inherent anticancer activity that complicates the interpretation of test results is minimized.
Collapse
|
|
16
|
Ashfaq UA, Saleem S, Masoud MS, Ahmad M, Nahid N, Bhatti R, Almatroudi A, Khurshid M. Rational design of multi epitope-based subunit vaccine by exploring MERS-COV proteome: Reverse vaccinology and molecular docking approach. PLoS One 2021; 16:e0245072. [PMID: 33534822 PMCID: PMC7857617 DOI: 10.1371/journal.pone.0245072] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2020] [Accepted: 12/21/2020] [Indexed: 02/06/2023] Open
Abstract
Middle East respiratory syndrome (MERS-COV), first identified in Saudi Arabia, was caused by a novel strain of coronavirus. Outbreaks were recorded from different regions of the world, especially South Korea and the Middle East, and were correlated with a 35% mortality rate. MERS-COV is a single-stranded, positive RNA virus that reaches the host by binding to the receptor of dipeptidyl-peptides. Because of the unavailability of the vaccine available for the protection from MERS-COV infection, the rapid case detection, isolation, infection prevention has been recommended to combat MERS-COV infection. So, vaccines for the treatment of MERS-COV infection need to be developed urgently. A possible antiviral mechanism for preventing MERS-CoV infection has been considered to be MERS-CoV vaccines that elicit unique T-cell responses. In the present study, we incorporated both molecular docking and immunoinformatic approach to introduce a multiepitope vaccine (MEP) against MERS-CoV by selecting 15 conserved epitopes from seven viral proteins such as three structural proteins (envelope, membrane, and nucleoprotein) and four non-structural proteins (ORF1a, ORF8, ORF3, ORF4a). The epitopes, which were examined for non-homologous to host and antigenicity, were selected on the basis of conservation between T-cell, B-cell, and IFN-γ epitopes. The selected epitopes were then connected to the adjuvant (β-defensin) at the N-terminal through an AAY linker to increase the immunogenic potential. Structural modelling and physiochemical characteristic were applied to the vaccine construct developed. Afterwards the structure has been successfully docked with antigenic receptor, Toll-like receptor 3 (TLR-3) and in-silico cloning ensures that its expression efficiency is legitimate. Nonetheless the MEP presented needs tests to verify its safety and immunogenic profile.
Collapse
Affiliation(s)
- Usman Ali Ashfaq
- Department of Bioinformatics and Biotechnology, Government College University, Faisalabad, Pakistan
- * E-mail:
| | - Saman Saleem
- Department of Bioinformatics and Biotechnology, Government College University, Faisalabad, Pakistan
| | - Muhammad Shareef Masoud
- Department of Bioinformatics and Biotechnology, Government College University, Faisalabad, Pakistan
| | - Matloob Ahmad
- Department of Chemistry, Government College University, Faisalabad, Pakistan
| | - Nazia Nahid
- Department of Bioinformatics and Biotechnology, Government College University, Faisalabad, Pakistan
| | - Rashid Bhatti
- Center of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan
| | - Ahmad Almatroudi
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah, Saudi Arabia
| | - Mohsin Khurshid
- Department of Microbiology, Government College University, Faisalabad, Pakistan
| |
Collapse
|
|
17
|
Ma CD, Imamura M, Talley DC, Rolt A, Xu X, Wang AQ, Le D, Uchida T, Osawa M, Teraoka Y, Li K, Hu X, Park SB, Chalasani N, Irvin PH, Dulcey AE, Southall N, Marugan JJ, Hu Z, Chayama K, Frankowski KJ, Liang TJ. Fluoxazolevir inhibits hepatitis C virus infection in humanized chimeric mice by blocking viral membrane fusion. Nat Microbiol 2020; 5:1532-1541. [PMID: 32868923 PMCID: PMC7677215 DOI: 10.1038/s41564-020-0781-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2020] [Accepted: 07/27/2020] [Indexed: 12/16/2022]
Abstract
Fluoxazolevir is an aryloxazole-based entry inhibitor of hepatitis C virus (HCV). We show that fluoxazolevir inhibits fusion of HCV with hepatic cells by binding HCV envelope protein 1 to prevent fusion. Nine of ten fluoxazolevir resistance-associated substitutions are in envelope protein 1, and four are in a putative fusion peptide. Pharmacokinetic studies in mice, rats and dogs revealed that fluoxazolevir localizes to the liver. A 4-week intraperitoneal regimen of fluoxazolevir in humanized chimeric mice infected with HCV genotypes 1b, 2a or 3 resulted in a 2-log reduction in viraemia, without evidence of drug resistance. In comparison, daclatasvir, an approved HCV drug, suppressed more than 3 log of viraemia but is associated with the emergence of resistance-associated substitutions in mice. Combination therapy using fluoxazolevir and daclatasvir cleared HCV genotypes 1b and 3 in mice. Fluoxazolevir combined with glecaprevir and pibrentasvir was also effective in clearing multidrug-resistant HCV replication in mice. Fluoxazolevir may be promising as the next generation of combination drug cocktails for HCV treatment.
Collapse
Affiliation(s)
- Christopher D Ma
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Michio Imamura
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
| | - Daniel C Talley
- Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA
| | - Adam Rolt
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Xin Xu
- Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA
| | - Amy Q Wang
- Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA
| | - Derek Le
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Takuro Uchida
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
| | - Mitsutaka Osawa
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
| | - Yuji Teraoka
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
| | - Kelin Li
- Center for Integrative Chemical Biology and Drug Discovery, University of North Carolina Eshelman School of Pharmacy, Chapel Hill, NC, USA
| | - Xin Hu
- Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA
| | - Seung Bum Park
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Nishanth Chalasani
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Parker H Irvin
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Andres E Dulcey
- Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA
| | - Noel Southall
- Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA
| | - Juan J Marugan
- Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA
| | - Zongyi Hu
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
| | - Kevin J Frankowski
- Center for Integrative Chemical Biology and Drug Discovery, University of North Carolina Eshelman School of Pharmacy, Chapel Hill, NC, USA
| | - Tsanyang Jake Liang
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
| |
Collapse
|
|
18
|
Okwor CIA, Oh JS, Crawley AM, Cooper CL, Lee SH. Expression of Inhibitory Receptors on T and NK Cells Defines Immunological Phenotypes of HCV Patients with Advanced Liver Fibrosis. iScience 2020; 23:101513. [PMID: 32920488 PMCID: PMC7492990 DOI: 10.1016/j.isci.2020.101513] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Revised: 07/23/2020] [Accepted: 08/26/2020] [Indexed: 12/12/2022] Open
Abstract
Chronic HCV can result in advanced liver disease, including cirrhosis. Patients with advanced fibrosis experience poor clinical outcomes and increased risk for hepatocellular carcinoma (HCC). These outcomes are, in part, a consequence of immune dysfunction. Increased inhibitory receptor and Galectin-9 (GAL-9) expression is a possible mechanism promoting lymphocyte dysfunction. In this study, we measured the expression of inhibitory receptors and GAL-9 on T/NK cells of patients with chronic HCV with no to moderate fibrosis (F0-F2) and advanced fibrosis (F3-F4). To analyze their co-expression, we employed t-SNE analysis. Notably, we found that F3-F4 patients had higher frequencies of >3 inhibitory receptor co-expression on NK cells. Moreover, F3-F4 patients manifest a higher frequency of NK cells co-expressing TIGIT and TIM-3, and CD4/NK cells co-expressing LAG-3 and GAL-9. In conclusion, we identified phenotypes of immune dysregulation that could explain the increased susceptibility to infection and HCC in patients with chronic HCV with advanced fibrosis.
Collapse
Affiliation(s)
| | - Jun Seok Oh
- Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa K1H 8M5, Canada
| | - Angela Marie Crawley
- Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa K1H 8M5, Canada
- Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa K1Y 4E9, Canada
- Division of Infectious Diseases, Ottawa Hospital-General Campus, Ottawa K1H 8L6, Canada
- The University of Ottawa Centre for Infection, Immunity, and Inflammation, Ottawa K1H 8M5, Canada
- Department of Biology, Carleton University, Ottawa K1S 5B6, Canada
| | - Curtis Lindsey Cooper
- Division of Infectious Diseases, Ottawa Hospital-General Campus, Ottawa K1H 8L6, Canada
- The University of Ottawa Centre for Infection, Immunity, and Inflammation, Ottawa K1H 8M5, Canada
- Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa K1Y 4E9, Canada
- Department of Medicine, University of Ottawa, Ottawa K1H 8M5, Canada
- School of Epidemiology and Public Health, University of Ottawa, Ottawa K1G 5Z3, Canada
| | - Seung-Hwan Lee
- Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa K1H 8M5, Canada
- The University of Ottawa Centre for Infection, Immunity, and Inflammation, Ottawa K1H 8M5, Canada
| |
Collapse
|
|
19
|
The Role of the Liver-Specific microRNA, miRNA-122 in the HCV Replication Cycle. Int J Mol Sci 2020; 21:ijms21165677. [PMID: 32784807 PMCID: PMC7460827 DOI: 10.3390/ijms21165677] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Revised: 08/04/2020] [Accepted: 08/05/2020] [Indexed: 02/08/2023] Open
Abstract
Hepatitis C virus (HCV) replication requires annealing of a liver specific microRNA, miR-122 to 2 sites on 5' untranslated region (UTR). While, microRNAs downregulate gene expression by binding to the 3' untranslated region of the target mRNA, in this case, the microRNA anneals to the 5'UTR of the viral genomes and upregulates the viral lifecycle. In this review, we explore the current understandings of the mechanisms by which miR-122 promotes the HCV lifecycle, and its contributions to pathogenesis. Annealing of miR-122 has been reported to (a) stimulate virus translation by promoting the formation of translationally active internal ribosome entry site (IRES) RNA structure, (b) stabilize the genome, and (c) induce viral genomic RNA replication. MiR-122 modulates lipid metabolism and suppresses tumor formation, and sequestration by HCV may influence virus pathogenesis. We also discuss the possible use of miR-122 as a biomarker for chronic hepatitis and as a therapeutic target. Finally, we discuss roles for miR-122 and other microRNAs in promoting other viruses.
Collapse
|
|
20
|
Khalid H, Ashfaq UA. Exploring HCV genome to construct multi-epitope based subunit vaccine to battle HCV infection: Immunoinformatics based approach. J Biomed Inform 2020; 108:103498. [PMID: 32621883 DOI: 10.1016/j.jbi.2020.103498] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Revised: 05/03/2020] [Accepted: 06/25/2020] [Indexed: 01/16/2023]
Abstract
Hepatitis C Virus (HCV) infection is a major cause of chronic liver disease, hepatocellular carcinoma, and the single most common indication for liver transplantation. HCV vaccines eliciting specific T-cell responses, have been considered as potent method to prevent HCV infection. Despite several reports on progress of vaccine, these vaccine failed in mediating clinical relevance activity against HCV in humans. In this study we integrated both immunoinformatic and molecular docking approach to present a multiepitope vaccine against HCV by designating 17 conserved epitopes from eight viral proteins such as Core protein, E1, E2, NS2, NS34A, NS4B, NS5A, and NS5B. The epitopes were prioritized based on conservation among epitopes of T cell, B cell and IFN-γ that were then scanned for non-homologous to host and antigenicity. The prioritized epitopes were then linked together by AAY linker and adjuvant (β-defensin) were attached at N-terminal to enhance immunogenic potential. The construct thus formed were subjected to structural modeling and physiochemical characteristics. The modeled structure were successfully docked to antigenic receptor TLR-3 and In-silico cloning confers the authenticity of its expression efficiency. However, the proposed construct need to be validate experimentally to ensure its safety and immunogenic profile.
Collapse
Affiliation(s)
- Hina Khalid
- Department of Bioinformatics and Biotechnology, Government College University, Faisalabad, Pakistan
| | - Usman Ali Ashfaq
- Department of Bioinformatics and Biotechnology, Government College University, Faisalabad, Pakistan.
| |
Collapse
|
|
21
|
Morgan TR. Hepatitis C Guidance 2019 Update: American Association for the Study of Liver Diseases-Infectious Diseases Society of America Recommendations for Testing, Managing, and Treating Hepatitis C Virus Infection. Hepatology 2020; 71:686-721. [PMID: 31816111 PMCID: PMC9710295 DOI: 10.1002/hep.31060] [Citation(s) in RCA: 523] [Impact Index Per Article: 104.6] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2019] [Accepted: 11/21/2019] [Indexed: 02/06/2023]
Affiliation(s)
| | - Timothy R. Morgan
- Chief of Hepatology Veterans Affairs Long Beach Healthcare System Long Beach CA
| | | |
Collapse
|
|
22
|
Nehme Z, Pasquereau S, Herbein G. Targeting histone epigenetics to control viral infections. HISTONE MODIFICATIONS IN THERAPY 2020. [PMCID: PMC7453269 DOI: 10.1016/b978-0-12-816422-8.00011-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
During the past decades, many studies have significantly broadened our understanding of complex virus-host interactions to control chromatin structure and dynamics.1, 2 However, the role and impact of such modifications during viral infections is not fully revealed. Indeed, this type of regulation is bidirectional between the virus and the host. While viral replication and gene expression are significantly impacted by histone modifications on the viral chromatin,3 studies have shown that some viral pathogens dynamically manipulate cellular epigenetic factors to enhance their own survival and pathogenesis, as well as escape the immune system defense lines.4 In this dynamic, histone posttranslational modifications (PTMs) appear to play fundamental roles in the regulation of chromatin structure and recruitment of other factors.5 Genuinely, those PTMs play a vital role in lytic infection, latency reinforcement, or, conversely, viral reactivation.6 In this chapter, we will examine and review the involvement of histone modifications as well as their potential manipulation to control infections during various viral life cycle stages, highlighting their prospective implications in the clinical management of human immunodeficiency virus (HIV), herpes simplex virus (HSV), human cytomegalovirus (HCMV), hepatitis B and C viruses (HBV and HCV, respectively), Epstein–Barr virus (EBV), and other viral diseases. Targeting histone modifications is critical in setting the treatment of chronic viral infections with both lytic and latent stages (HIV, HCMV, HSV, RSV), virus-induced cancers (HBV, HCV, EBV, KSHV, HPV), and epidemic/emerging viruses (e.g. influenza virus, arboviruses).
Collapse
|
|
23
|
Lee H, Jarhad DB, Yu J, Lee C, Jeong LS. Asymmetric Synthesis of 2'- C-Methyl-4'-selenonucleosides as Anti-Hepatitis C Virus Agents. J Org Chem 2019; 84:14414-14426. [PMID: 31608633 DOI: 10.1021/acs.joc.9b01462] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
In search of a new template for anti-hepatitis C virus (HCV) agents, we designed and synthesized the 2'-C-methyl-4'-selenopyrimidine and -purine nucleosides and their phosphoramidate prodrugs to replace a furanose oxygen of anti-HCV nucleos(t)ides with a selenium atom on the basis that selenium is a chemical isostere of oxygen. These nucleosides are expected to show different physicochemical properties such as better lipophilicity which might enhance the penetration across cell membranes and the conformational constraint induced by a bulky selenium atom in the sugar ring. The 2'-C-methyl-4'-selenopyrimidine and -purine nucleosides 8 and 9 were synthesized from 2-C-methyl-d-ribono-γ-lactone (14) via construction of 2-C-methyl-d-selenosugar 18 through C-4 epimerization and SN2 cyclization with Se2- as key steps. The key 4'-selenosugar was converted to the 2'-C-methyl-4'-selenopyrimidine and -purine nucleosides using Pummerer-type rearrangement and Vorbrüggen glycosylation, respectively. In addition, the ProTide strategy has been applied to synthesize the adenine and uracil phosphoramidate derivatives 10a and 10b to overcome the limitations associated with parent nucleosides such as inefficient conversion to their corresponding 5'-monophosphate form and poor cellular uptake. The regio- and stereochemistry of 4'-selenonucleosides were confirmed by 2D NOESY NMR spectroscopy and X-ray crystallography. None of the final pyrimidine and purine nucleosides and their prodrugs exhibited significant anti-HCV activity up to 100 μM.
Collapse
Affiliation(s)
- Hyejin Lee
- Research Institute of Pharmaceutical Sciences, College of Pharmacy , Seoul National University , Seoul 08820 , Korea
| | - Dnyandev B Jarhad
- Research Institute of Pharmaceutical Sciences, College of Pharmacy , Seoul National University , Seoul 08820 , Korea
| | - Jinha Yu
- Research Institute of Pharmaceutical Sciences, College of Pharmacy , Seoul National University , Seoul 08820 , Korea
| | - Choongho Lee
- College of Pharmacy , Dongguk University , Goyang , Gyeonggi-do 10326 , Korea
| | - Lak Shin Jeong
- Research Institute of Pharmaceutical Sciences, College of Pharmacy , Seoul National University , Seoul 08820 , Korea
| |
Collapse
|
|
24
|
Ciccozzi M, Lai A, Zehender G, Borsetti A, Cella E, Ciotti M, Sagnelli E, Sagnelli C, Angeletti S. The phylogenetic approach for viral infectious disease evolution and epidemiology: An updating review. J Med Virol 2019; 91:1707-1724. [PMID: 31243773 DOI: 10.1002/jmv.25526] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2019] [Accepted: 06/24/2019] [Indexed: 12/16/2022]
Abstract
In the last decade, the phylogenetic approach is recurrent in molecular evolutionary analysis. On 12 May, 2019, about 2 296 213 papers are found, but typing "phylogeny" or "epidemiology AND phylogeny" only 199 804 and 20 133 are retrieved, respectively. Molecular epidemiology in infectious diseases is widely used to define the source of infection as so as the ancestral relationships of individuals sampled from a population. Coalescent theory and phylogeographic analysis have had scientific application in several, recent pandemic events, and nosocomial outbreaks. Hepatitis viruses and immunodeficiency virus (human immunodeficiency virus) have been largely studied. Phylogenetic analysis has been recently applied on Polyomaviruses so as in the more recent outbreaks due to different arboviruses type as Zika and chikungunya viruses discovering the source of infection and the geographic spread. Data on sequences isolated by the microorganism are essential to apply the phylogenetic tools and research in the field of infectious disease phylodinamics is growing up. There is the need to apply molecular phylogenetic and evolutionary methods in areas out of infectious diseases, as translational genomics and personalized medicine. Lastly, the application of these tools in vaccine strategy so as in antibiotic and antiviral researchers are encouraged.
Collapse
Affiliation(s)
- Massimo Ciccozzi
- Unit of Medical Statistics and Molecular Epidemiology, University Campus Bio-Medico of Rome, Rome, Italy
| | - Alessia Lai
- Department of Biomedical and Clinical Sciences 'L. Sacco', University of Milan, Milan, Italy
| | - Gianguglielmo Zehender
- Department of Biomedical and Clinical Sciences 'L. Sacco', University of Milan, Milan, Italy
| | - Alessandra Borsetti
- National HIV/AIDS Research Center, Istituto Superiore di Sanità, Roma, Italy
| | - Eleonora Cella
- Unit of Medical Statistics and Molecular Epidemiology, University Campus Bio-Medico of Rome, Rome, Italy
| | - Marco Ciotti
- Laboratory of Molecular Virology, Polyclinic Tor Vergata Foundation, Rome, Italy
| | - Evangelista Sagnelli
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Caterina Sagnelli
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Silvia Angeletti
- Unit of Clinical Laboratory Science, University Campus Bio-Medico of Rome, Rome, Italy
| |
Collapse
|
|
25
|
Convery O, Gargan S, Kickham M, Schroder M, O'Farrelly C, Stevenson NJ. The hepatitis C virus (HCV) protein, p7, suppresses inflammatory responses to tumor necrosis factor (TNF)-α via signal transducer and activator of transcription (STAT)3 and extracellular signal-regulated kinase (ERK)-mediated induction of suppressor of cytokine signaling (SOCS)3. FASEB J 2019; 33:8732-8744. [PMID: 31163989 DOI: 10.1096/fj.201800629rr] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Viruses use a spectrum of immune evasion strategies that enable infection and replication. The acute phase of hepatitis C virus (HCV) infection is characterized by nonspecific and often mild clinical symptoms, suggesting an immunosuppressive mechanism that, unless symptomatic liver disease presents, allows the virus to remain largely undetected. We previously reported that HCV induced the regulatory protein suppressor of cytokine signaling (SOCS)3, which inhibited TNF-α-mediated inflammatory responses. However, the mechanism by which HCV up-regulates SOCS3 remains unknown. Here we show that the HCV protein, p7, enhances both SOCS3 mRNA and protein expression. A p7 inhibitor reduced SOCS3 induction, indicating that p7's ion channel activity was required for optimal up-regulation of SOCS3. Short hairpin RNA and chemical inhibition revealed that both the Janus kinase-signal transducer and activator of transcription (JAK-STAT) and MAPK pathways were required for p7-mediated induction of SOCS3. HCV-p7 expression suppressed TNF-α-mediated IκB-α degradation and subsequent NF-κB promoter activity, revealing a new and functional, anti-inflammatory effect of p7. Together, these findings identify a molecular mechanism by which HCV-p7 induces SOCS3 through STAT3 and ERK activation and demonstrate that p7 suppresses proinflammatory responses to TNF-α, possibly explaining the lack of inflammatory symptoms observed during early HCV infection.-Convery, O., Gargan, S., Kickham, M., Schroder, M., O'Farrelly, C., Stevenson, N. J. The hepatitis C virus (HCV) protein, p7, suppresses inflammatory responses to tumor necrosis factor (TNF)-α via signal transducer and activator of transcription (STAT)3 and extracellular signal-regulated kinase (ERK)-mediated induction of suppressor of cytokine signaling (SOCS)3.
Collapse
Affiliation(s)
- Orla Convery
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
| | - Siobhan Gargan
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
| | | | | | - Cliona O'Farrelly
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.,School of Medicine, Trinity College Dublin, Dublin, Ireland
| | - Nigel J Stevenson
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
| |
Collapse
|
|
26
|
Casey JL, Feld JJ, MacParland SA. Restoration of HCV-Specific Immune Responses with Antiviral Therapy: A Case for DAA Treatment in Acute HCV Infection. Cells 2019; 8:cells8040317. [PMID: 30959825 PMCID: PMC6523849 DOI: 10.3390/cells8040317] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Revised: 03/26/2019] [Accepted: 03/30/2019] [Indexed: 12/11/2022] Open
Abstract
Worldwide, 71 million individuals are chronically infected with Hepatitis C Virus (HCV). Chronic HCV infection can lead to potentially fatal outcomes including liver cirrhosis and hepatocellular carcinoma. HCV-specific immune responses play a major role in viral control and may explain why approximately 20% of infections are spontaneously cleared before the establishment of chronicity. Chronic infection, associated with prolonged antigen exposure, leads to immune exhaustion of HCV-specific T cells. These exhausted T cells are unable to control the viral infection. Before the introduction of direct acting antivirals (DAAs), interferon (IFN)-based therapies demonstrated successful clearance of viral infection in approximately 50% of treated patients. New effective and well-tolerated DAAs lead to a sustained virological response (SVR) in more than 95% of patients regardless of viral genotype. Researchers have investigated whether treatment, and the subsequent elimination of HCV antigen, can reverse this HCV-induced exhausted phenotype. Here we review literature exploring the restoration of HCV-specific immune responses following antiviral therapy, both IFN and DAA-based regimens. IFN treatment during acute HCV infection results in greater immune restoration than IFN treatment of chronically infected patients. Immune restoration data following DAA treatment in chronically HCV infected patients shows varied results but suggests that DAA treatment may lead to partial restoration that could be improved with earlier administration. Future research should investigate immune restoration following DAA therapies administered during acute HCV infection.
Collapse
Affiliation(s)
- Julia L Casey
- Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, Canada.
| | - Jordan J Feld
- Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, Canada.
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 2C4, Canada.
| | - Sonya A MacParland
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 2C4, Canada.
- Departments of Laboratory Medicine & Pathobiology and Immunology, University of Toronto, Toronto, ON M5S 1A1, Canada.
| |
Collapse
|
|
27
|
Ikram A, Zaheer T, Awan FM, Obaid A, Naz A, Hanif R, Paracha RZ, Ali A, Naveed AK, Janjua HA. Exploring NS3/4A, NS5A and NS5B proteins to design conserved subunit multi-epitope vaccine against HCV utilizing immunoinformatics approaches. Sci Rep 2018; 8:16107. [PMID: 30382118 PMCID: PMC6208421 DOI: 10.1038/s41598-018-34254-5] [Citation(s) in RCA: 64] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2018] [Accepted: 10/05/2018] [Indexed: 12/22/2022] Open
Abstract
Hepatitis C virus (HCV) vaccines, designed to augment specific T-cell responses, have been designated as an important aspect of effective antiviral treatment. However, despite the current satisfactory progress of these vaccines, extensive past efforts largely remained unsuccessful in mediating clinically relevant anti-HCV activity in humans. In this study, we used a series of immunoinformatics approaches to propose a multiepitope vaccine against HCV by prioritizing 16 conserved epitopes from three viral proteins (i.e., NS34A, NS5A, and NS5B). The prioritised epitopes were tested for their possible antigenic combinations with each other along with linker AAY using structural modelling and epitope-epitope interactions analysis. An adjuvant (β-defensin) at the N-terminal of the construct was added to enhance the immunogenicity of the vaccine construct. Molecular dynamics (MD) simulation revealed the most stable structure of the proposed vaccine. The designed vaccine is potentially antigenic in nature and can form stable and significant interactions with Toll-like receptor 3 and Toll-like receptor 8. The proposed vaccine was also subjected to an in silico cloning approach, which confirmed its expression efficiency. These analyses suggest that the proposed vaccine can elicit specific immune responses against HCV; however, experimental validation is required to confirm the safety and immunogenicity profile of the proposed vaccine construct.
Collapse
Affiliation(s)
- Aqsa Ikram
- Department of Industrial Biotechnology, Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), Islamabad, Pakistan
| | - Tahreem Zaheer
- Department of Industrial Biotechnology, Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), Islamabad, Pakistan
| | - Faryal Mehwish Awan
- Department of Industrial Biotechnology, Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), Islamabad, Pakistan
| | - Ayesha Obaid
- Department of Industrial Biotechnology, Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), Islamabad, Pakistan
| | - Anam Naz
- Department of Industrial Biotechnology, Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), Islamabad, Pakistan
| | - Rumeza Hanif
- Department of Healthcare Biotechnology, Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), Islamabad, Pakistan
| | - Rehan Zafar Paracha
- Research Center for Modeling & Simulation (RCMS), National University of Sciences & Technology (NUST), Islamabad, Pakistan
| | - Amjad Ali
- Department of Industrial Biotechnology, Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), Islamabad, Pakistan
| | - Abdul Khaliq Naveed
- Islamic International Medical College, Riphah International University Rawalpindi, Islamabad, Pakistan
| | - Hussnain Ahmed Janjua
- Department of Industrial Biotechnology, Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), Islamabad, Pakistan.
| |
Collapse
|
|
28
|
Dias C, Pipa S, Mota M. Acute hepatitis C from heterosexual transmission. IDCases 2018; 14:e00448. [PMID: 30191131 PMCID: PMC6125761 DOI: 10.1016/j.idcr.2018.e00448] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2018] [Revised: 08/29/2018] [Accepted: 08/29/2018] [Indexed: 12/23/2022] Open
Abstract
The diagnosis of acute hepatitis C (HCV) infection is rare since the majority of cases are asymptomatic, which makes the infection usually detected in a chronic phase, most of the time using serological tests. The main route of HCV transmission is percutaneous, with sexual transmission occurring more often in men who have sex with men. The analytical alterations of acute hepatitis C are varied but usually present with ALT elevation higher than AST, very rarely with hepatic insufficiency. We report a case of a patient with a clinical and analytical picture compatible with toxic acute hepatitis, accompanied by hepatic insufficiency, with negative serology for hepatotropic viruses and with no history compatible with the use of substances with hepatic toxicity other than alcohol. During the diagnostic investigation it was concluded that the patient had acute HCV hepatitis and that the transmission route was heterosexual.
Collapse
Affiliation(s)
- Cátia Dias
- Department of Internal Medicine, Centro Hospitalar de Vila Nova de Gaia, Espinho, Portugal
| | - Sara Pipa
- Department of Internal Medicine, Centro Hospitalar de Vila Nova de Gaia, Espinho, Portugal
| | - Margarida Mota
- Department of Internal Medicine, Centro Hospitalar de Vila Nova de Gaia, Espinho, Portugal
| |
Collapse
|
|
29
|
Johannessen I, Danial J, Smith DB, Richards J, Imrie L, Rankin A, Willocks LJ, Evans C, Leen C, Gibson P, Simmonds P, Goldberg D, McCallum A, Roy K. Molecular and epidemiological evidence of patient-to-patient hepatitis C virus transmission in a Scottish emergency department. J Hosp Infect 2017; 98:412-418. [PMID: 29242141 DOI: 10.1016/j.jhin.2017.12.006] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2017] [Accepted: 12/06/2017] [Indexed: 12/12/2022]
Abstract
BACKGROUND Transmission of hepatitis C virus (HCV) in the healthcare setting is rare. Routine infection prevention and control measures mean that this should be a preventable 'never event'. AIM To investigate the diagnosis of acute healthcare-associated HCV infection. METHODS Epidemiological and molecular investigation of a case of acute HCV infection associated with nosocomial exposure. FINDINGS Detailed investigation of the treatment history of a patient with acute HCV infection identified transmission from a co-attending patient in an emergency department as the likely source; this possibility was confirmed by virus sequence analysis. The precise route of transmission was not identified, though both patient and source had minimally invasive healthcare interventions. Review of infection, prevention and control identified potentially contributory factors in the causal pathway including hand hygiene, inappropriate use of personal protective equipment, and blood contamination of the surface of the departmental blood gas analyser. CONCLUSION We provide molecular and epidemiological evidence of HCV transmission between patients in an emergency department that was made possible by environmental contamination. Patients with HCV infection are higher users of emergency care than the general population and a significant proportion of those affected remain unknown and/or infectious. Equipment, departmental design, staff behaviour, and patient risk require regular review to minimize the risk of nosocomial HCV transmission.
Collapse
Affiliation(s)
- I Johannessen
- NHS Lothian Laboratory Medicine (Virology), Royal Infirmary of Edinburgh, Edinburgh, UK.
| | - J Danial
- NHS Lothian Infection Prevention and Control Service, Royal Infirmary of Edinburgh, Edinburgh, UK
| | - D B Smith
- Centre for Immunity, Infection and Evolution, University of Edinburgh, Edinburgh, UK
| | - J Richards
- NHS Lothian Infection Prevention and Control Service, Royal Infirmary of Edinburgh, Edinburgh, UK
| | - L Imrie
- Infection Prevention and Control Group, Health Protection Scotland, Glasgow, UK
| | - A Rankin
- Infection Prevention and Control Group, Health Protection Scotland, Glasgow, UK
| | - L J Willocks
- NHS Lothian Public Health and Health Policy, Waverley Gate, Edinburgh, UK
| | - C Evans
- NHS Lothian Public Health and Health Policy, Waverley Gate, Edinburgh, UK
| | - C Leen
- NHS Lothian Regional Infectious Diseases Unit, Western General Hospital, Edinburgh, UK
| | - P Gibson
- NHS Lothian Department of Renal Medicine, Royal Infirmary of Edinburgh, Edinburgh, UK
| | - P Simmonds
- Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - D Goldberg
- Blood-Borne Virus Group, Health Protection Scotland, Glasgow, UK
| | - A McCallum
- NHS Lothian Public Health and Health Policy, Waverley Gate, Edinburgh, UK
| | - K Roy
- Blood-Borne Virus Group, Health Protection Scotland, Glasgow, UK
| |
Collapse
|
|
30
|
Hernández-Bartolomé Á, López-Rodríguez R, García-Buey L, Martín-Vílchez S, Rodríguez-Muñoz Y, Borque MJ, González-Moreno L, Real-Martínez Y, Mendoza-Ridruejo J, Martín-Pérez E, Moreno-Otero R, Sanz-Cameno P. Intrahepatic angiopoietin-2 correlates with chronic hepatitis C progression and is induced in hepatitis C virus replicon systems. Liver Int 2017; 37:1148-1156. [PMID: 28027429 DOI: 10.1111/liv.13352] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2016] [Accepted: 12/13/2016] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS Chronic hepatitis C (CHC) is a major cause of cirrhosis and hepatocellular carcinoma and angiogenesis is closely related to the pathogenesis and progression of different chronic liver diseases (CLD). Thus, the intrahepatic expression of angiopoietins 1 and 2 (Ang1 and Ang2), as relevant mediators of pathological angiogenesis in several CLD, was investigated. In addition, the differential influence of structural and non-structural genomic regions of HCV on the expression of angiopoietins and the possible signalling involved were studied. METHODS Ang1 and Ang2 expression was evaluated by western blotting and enzyme-linked immunosorbent assay (ELISA) in liver homogenates of CHC patients (n=47) and uninfected subjects (n=8). Their association with disease progression (according to METAVIR classification) was assessed by Spearman's correlation. Statistical differences among the expression of angiopoietins at different CHC stages were calculated by Mann-Whitney U-test. Finally, the in vitro expression of Angiopoietins in HCV replicons (complete or non-structural subgenomic) and the main signalling pathways involved were also examined. RESULTS Ang2 levels were significantly higher in the liver of CHC patients compared to controls and significantly correlated with inflammation and fibrosis. Accordingly, an increased expression of Ang2 was found in all HCV replicons tested. Interestingly, the inhibition of MEK and PI3K signalling pathways exerted differential effects on Ang2 expression concerning to the genomic region of HCV. CONCLUSIONS Hepatitis C virus induces Ang2 expression in hepatocytes through different signalling routes which may lead to the disregulation of vascular homeostasis in the liver. Thus, pharmacologic intervention on Ang2 signalling might constitute an important therapeutic tool.
Collapse
Affiliation(s)
| | | | - Luisa García-Buey
- Liver Unit, Instituto Investigación Sanitaria Princesa, IIS-IP, Madrid, Spain.,CIBERehd, Instituto de Salud Carlos III, ISCIII, Madrid, Spain
| | | | | | - María Jesús Borque
- Molecular Biology Unit, Instituto de Investigación Sanitaria Princesa, IIS-IP, Madrid, Spain
| | | | | | | | - Elena Martín-Pérez
- Digestive Surgery Service, Instituto Investigación Sanitaria Princesa, IIS-IP, Madrid, Spain
| | - Ricardo Moreno-Otero
- Liver Unit, Instituto Investigación Sanitaria Princesa, IIS-IP, Madrid, Spain.,CIBERehd, Instituto de Salud Carlos III, ISCIII, Madrid, Spain
| | - Paloma Sanz-Cameno
- Liver Unit, Instituto Investigación Sanitaria Princesa, IIS-IP, Madrid, Spain.,CIBERehd, Instituto de Salud Carlos III, ISCIII, Madrid, Spain
| |
Collapse
|
|
31
|
Spataro C, Afdhal S, Weinstein AA, Escheik C, Austin P, Brodie K, Gerber L, Younossi ZM. Fatigue and Hepatitis C: a focus group study. ACTA ACUST UNITED AC 2017. [DOI: 10.4081/qrmh.2017.6698] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Fatigue is often undiagnosed by health professionals as it is still seen as a nonspecific symptom without standard evaluations and effective treatments. Fatigue is present across many different diseases and has a profound effect on the quality of life of patients. However, it is still difficult to measure because of the lack of specificity of currently used self-report instruments. Patients with chronic hepatitis C infection, (HCV), experience fatigue as one of the most debilitating symptoms. The purpose of this study was to explore the types and dimensions of fatigue experienced by patients with HCV, identify specific terms they use to describe fatigue and assess how it influences everyday activities. Sixteen individuals with HCV (56% female, aged 58.1 ± 3.7 years) participated in three focus group sessions. The focus group sessions lasted between 60 and 90 minutes and were digitally recorded via audiotapes. Recorded focus groups’ audiotapes were analyzed through thematic analyses. The analysis suggested two primary categories of fatigue experiences. These were: capacity and engagement in activity. Capacity refers specifically to an individual’s sense of how much energy they have to do life activities or their maximum ability to produce energy. The word energy is the ability to perform work and includes one’s ability to access or utilize, expend, and restore it. The phrase engagement in activity, comprised two domains: initiation (getting started or being motivated) and personal satisfaction (value of the activity). This investigation helped to identify important domains of fatigue experienced by those with HCV. The findings augment our current understanding of fatigue for this group because the domains of fatigue and the terms used to describe it are not commonly represented in the most frequently used fatigue assessments.
Collapse
|
|
32
|
Sofosbuvir based treatment of chronic hepatitis C genotype 3 infections-A Scandinavian real-life study. PLoS One 2017; 12:e0179764. [PMID: 28704381 PMCID: PMC5509146 DOI: 10.1371/journal.pone.0179764] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2017] [Accepted: 06/02/2017] [Indexed: 12/22/2022] Open
Abstract
Background and aims Chronic hepatitis C virus (HCV) genotype 3 infection with advanced liver disease has emerged as the most challenging to treat. We retrospectively assessed the treatment outcome of sofosbuvir (SOF) based regimes for treatment of HCV genotype 3 infections in a real life setting in Scandinavia. Methods Consecutive patients with chronic HCV genotype 3 infection were enrolled at 16 treatment centers in Denmark, Sweden, Norway and Finland. Patients who had received a SOF containing regimen were included. The fibrosis stage was evaluated by liver biopsy or transient liver elastography. The following treatments were given according availability and local guidelines: 1) SOF + ribavirin (RBV) for 24 weeks, 2) SOF + daclatasvir (DCV) +/-RBV for 12–24 weeks, 3) SOF + pegylated interferon alpha (peg-IFN-α) + RBV for 12 weeks or 4) SOF/ledipasvir (LDV) + RBV for 12–16 weeks. The primary endpoint was sustained virological response (SVR) assessed at week 12 (SVR12) after end of treatment. Results We included 316 patients with a mean age of 55 years (range 24–79), 70% men, 49% treatment experienced, 58% with compensated cirrhosis and 12% with decompensated cirrhosis.In the modified intention to treat (mITT) population SVR12 was achieved in 284/311 (91%) patients. Among 26 treatment failures, five had non-response, 3 breakthrough and 18 relapse. Five patients were not included in the mITT population. Three patients died from reasons unrelated to treatment and two were lost to follow-up. The SVR12 rate was similar for all treatment regimens, but lower in men (p = 0.042), and in patients with decompensated liver disease (p = 0.004). Conclusion We found that sofosbuvir based treatment in a real-life setting could offer SVR rates exceeding 90% in patients with HCV genotype 3 infection and advanced liver disease.
Collapse
|
|
33
|
Dirchwolf M, Marciano S, Mauro E, Ruf AE, Rezzonico L, Anders M, Chiodi D, Petta NG, Borzi S, Tanno F, Ridruejo E, Barreyro F, Shulman C, Plaza P, Carbonetti R, Tadey L, Schroder T, Fainboim H. Clinical epidemiology of acute hepatitis C in South America. J Med Virol 2017; 89:276-283. [PMID: 27253181 DOI: 10.1002/jmv.24588] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/31/2016] [Indexed: 12/14/2022]
Abstract
There is scarce data pertaining to acute hepatitis C (aHC) infection in South America. We aimed to describe clinical characteristics and evolution of aHC in a South American cohort. A retrospective survey was conducted at 13 hepatology units. All patients ≥16 years old with aHC diagnosis were included. Demographic, clinical and outcome information were registered in a standardized ad hoc questionnaire. Sixty-four patients were included. The majority were middle-aged (median age: 46 years) and female (65.6%); most of them were symptomatic at diagnosis (79.6%). HCV-1 was the most prevalent genotype (69.2%). Five patients had liver failure: three cases of severe acute hepatitis, one case of fulminant hepatitis and one case of acute-on-chronic liver failure. Nosocomial exposure was the most prevalent risk factor. Evolution was assessed in 46 patients. In the untreated cohort, spontaneous resolution occurred in 45.8% and was associated with higher values of AST/ALT and with the absence of intermittent HCV RNA viremia (P = 0.01, 0.05, and 0.01, respectively). In the treated cohort, sustained virological response was associated with nosocomial transmission and early treatment initiation (P = 0.04 each). The prevalence of nosocomial transmission in this South-American cohort of aHC stresses the importance of following universal precautions to prevent HCV infection. J. Med. Virol. 89:276-283, 2017. © 2016 Wiley Periodicals, Inc.
Collapse
Affiliation(s)
- Melisa Dirchwolf
- Hepatopatías Infecciosas, Hospital F.J. Muñiz, Buenos Aires, Argentina
| | | | - Ezequiel Mauro
- Liver Unit, Hospital Italiano de Buenos, Buenos Aires, Argentina
| | - Andrés Eduardo Ruf
- Fundación para la Docencia e Investigación de las Enfermedades del Hígado (FUNDIEH), Buenos Aires, Argentina
| | - Lucrecia Rezzonico
- Hepatología, Hospital de la Asociación Médica Dr. Felipe Glasman, Bahía Blanca, Buenos Aires, Argentina
| | - Margarita Anders
- Unidad de Hepatología y Trasplante Hepático, Hospital Alemán, Buenos Aires, Argentina
| | - Daniela Chiodi
- Hospital de Clínicas, Facultad de Medicina, UDELAR, Montevideo, Uruguay
| | - Néstor Gill Petta
- Servicio de Gastroenterología y Hepatología, Hospital Central del Instituto de Previsión Social de Asunción, Paraguay
| | - Silvia Borzi
- Sección Hepatología, HIGA Prof. Dr. Rodolfo Rossi, La Plata Buenos Aires, Argentina
| | - Federico Tanno
- Servicio de Hepatología y Gastroenterología, Hospital Provincial del Centenario de Rosario, Argentina
| | - Ezequiel Ridruejo
- Sección Hepatología, Centro de Educación Médica e Investigaciones Clínicas Norberto Quirno "CEMIC", Unidad de Hepatología y Trasplante Hepático, Hospital Universitario Austral, Buenos Aires, Argentina
| | - Fernando Barreyro
- Laboratorio de Microbiología, Facultad de Química y Ciencias Naturales Universidad de Misiones, Posadas, Argentina
| | | | - Pablo Plaza
- Gastroenterología y Hepatología, Salta Capital, Argentina
| | - Rodolfo Carbonetti
- Gastroenterología y Hepatología, Hospital de Clínicas Nicolás Avellaneda, Tucumán, Argentina
| | - Luciana Tadey
- Unidad de Virología, Hospital F.J. Muñiz, Buenos Aires, Argentina
| | - Teresa Schroder
- Hepatopatías Infecciosas, Hospital F.J. Muñiz, Buenos Aires, Argentina
| | - Hugo Fainboim
- Hepatopatías Infecciosas, Hospital F.J. Muñiz, Buenos Aires, Argentina
| |
Collapse
|
|
34
|
Ragonnet R, Deuffic-Burban S, Boesecke C, Guiguet M, Lacombe K, Guedj J, Rockstroh JK, Yazdanpanah Y. Estimating the Time to Diagnosis and the Chance of Spontaneous Clearance During Acute Hepatitis C in Human Immunodeficiency Virus-Infected Individuals. Open Forum Infect Dis 2017; 4:ofw235. [PMID: 28480234 PMCID: PMC5414115 DOI: 10.1093/ofid/ofw235] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2016] [Revised: 10/16/2016] [Accepted: 10/28/2016] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND Hepatitis C virus (HCV) infection is often asymptomatic, and the date of infection is almost impossible to determine. Furthermore, spontaneous clearance (SC) may occur, but little is known about its time of occurrence. METHODS Data on human immunodeficiency virus (HIV)-HCV coinfected individuals were used to inform a stochastic simulation model of HCV viral load kinetics, alanine aminotransferase (ALT), and HCV antibodies during acute hepatitis C. The dates of diagnosis and potential SC were estimated through a Bayesian approach. Hepatitis C virus diagnosis was assumed to be based on an elevated ALT level detected during a control visit for HIV-infected individuals, which occurred every 3 months (scenario A) or every 6 months (scenario B). RESULTS We found that HCV diagnosis occurred after a median of 115 days and 170 days of infection in scenarios A and B, respectively. Among spontaneous clearers, SC occurred after a median time of 184 days after infection. Seven percent (scenario B) to 10% (scenario A) of SCs appeared more than 6 months after diagnosis, and 3% (both scenarios) of SCs appeared more than 1 year after diagnosis. CONCLUSIONS Acute hepatitis C diagnosis occurs late in HIV-HCV coinfected individuals. Screening for HCV in HIV-infected individuals should be performed frequently to reduce delays. Our findings about late occurrence of SC support "wait and see" strategies for treatment initiation from an individual basis. However, early treatment initiation may reduce HCV transmission.
Collapse
Affiliation(s)
- Romain Ragonnet
- Institut National de la Santé et de la Recherche Médicale (INSERM), Infection, Antimicrobiens, Modélisation, Evolution, Unité Mixte de Recherche (UMR) 1137, Paris, France; Université Paris Diderot, Sorbonne Paris Cité, France.,University of Melbourne, Department of Medicine, Dentistry and Health Sciences, Australia
| | - Sylvie Deuffic-Burban
- Institut National de la Santé et de la Recherche Médicale (INSERM), Infection, Antimicrobiens, Modélisation, Evolution, Unité Mixte de Recherche (UMR) 1137, Paris, France; Université Paris Diderot, Sorbonne Paris Cité, France.,Université de Lille, INSERM, Centre Hospitalier Universitaire Lille, U995 - Lille Inflammation Research International Center, France
| | - Christoph Boesecke
- Department of Internal Medicine 1, Rheinische Friedrich-Wilhelms University Bonn, Germany.,German Centre of Infection Research (DZIF), partner site Cologne-Bonn, Germany
| | - Marguerite Guiguet
- Sorbonne Universités, Université Pierre et Marie Curie, Université Paris 06, INSERM, Institut Pierre Louis d'Épidémiologie et de Santé Publique (UMRS 1136), France
| | - Karine Lacombe
- Sorbonne Universités, Université Pierre et Marie Curie, Université Paris 06, INSERM, Institut Pierre Louis d'Épidémiologie et de Santé Publique (UMRS 1136), France.,Service de Maladies Infectieuses et Tropicales, Hôpital Saint-Antoine, Paris, France
| | - Jeremie Guedj
- Institut National de la Santé et de la Recherche Médicale (INSERM), Infection, Antimicrobiens, Modélisation, Evolution, Unité Mixte de Recherche (UMR) 1137, Paris, France; Université Paris Diderot, Sorbonne Paris Cité, France
| | - Jürgen K Rockstroh
- Department of Internal Medicine 1, Rheinische Friedrich-Wilhelms University Bonn, Germany.,German Centre of Infection Research (DZIF), partner site Cologne-Bonn, Germany
| | - Yazdan Yazdanpanah
- Institut National de la Santé et de la Recherche Médicale (INSERM), Infection, Antimicrobiens, Modélisation, Evolution, Unité Mixte de Recherche (UMR) 1137, Paris, France; Université Paris Diderot, Sorbonne Paris Cité, France.,Service de Maladies Infectieuses et Tropicales, Hôpital Bichat Claude Bernard, Paris, France
| |
Collapse
|
|
35
|
Prevalence of Hepatitis C Virus Infection and Its Risk Factors among Patients Attending Rwanda Military Hospital, Rwanda. BIOMED RESEARCH INTERNATIONAL 2017; 2017:5841272. [PMID: 28246598 PMCID: PMC5299157 DOI: 10.1155/2017/5841272] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/24/2016] [Revised: 12/07/2016] [Accepted: 12/18/2016] [Indexed: 12/19/2022]
Abstract
In Rwanda, the prevalence of viral hepatitis (HCV) is poorly understood. The current study investigated the prevalence and risk factors of HCV infection in Rwanda. A total of 324 patients attending Rwanda Military Hospital were randomly selected and a questionnaire was administered to determine the risk factors. Blood was collected and screened for anti-HCV antibodies and seropositive samples were subjected to polymerase chain reaction method. Hematology abnormalities in the HCV infected patients were also investigated. Anti-HCV antibody and active HCV infection were found in 16.0% and 9.6% of total participants, respectively. Prevalence was highest (28.4%; 19/67) among participants above 55 years and least (2.4%; 3/123) among younger participants (18-35 years). There was a significant (P = 0.031) relationship between place of residence and HCV infection with residents of Southern Province having significantly higher prevalence. The hematological abnormalities observed in the HCV infected patients included leukopenia (48.4%; 15/52), neutropenia (6.5%; 2/52), and thrombocytopenia (25.8%; 8/52). The HCV infection was significantly higher in the older population (>55 years) and exposure to injection from traditional practitioners was identified as a significant (P = 0.036) risk factor of infection. Further studies to determine the factors causing the high prevalence of HCV in Rwanda are recommended.
Collapse
|
|
36
|
Shoraka S, Mohebbi SR, Hosseini SM, Hosseini Razavi A, Ghaemi A, Kazemian S, Rostami-Nejad M. Interleukin-21 rs2055979 and Interleukin-21 receptor rs3093390 genetic variants and hepatitis C virus chronic infection. GASTROENTEROLOGY AND HEPATOLOGY FROM BED TO BENCH 2017; 10:S154-S160. [PMID: 29511486 PMCID: PMC5838195] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
AIM The aim of this case-control study was to investigate association of G/T IL-21 (rs2055979) and C/T IL-21R (rs3093390) gene polymorphisms with chronic hepatitis C virus in Iranian Patients. BACKGROUND Interleukin 21 (IL-21) has a significant function in the regulation of cellular immune responses. Its exclusive receptor, IL-21R, expressed on the surface of T, B and NK cells and is important for the proliferation and differentiation of these immune cells. Hence, it was suggested to be involved in response to viral infections. METHODS This study follows a case-control study design and blood samples were collected from 290 patients with chronic HCV and 290 controls for both genes. Genomic DNA was extracted and then for each position, SNP was genotyped by the dedicated PCR and restriction fragment length polymorphism (RFLP) method. The results were analyzed by SPSS software using logistic regression and Chi-square tests. RESULTS Genotype frequencies of GG, GT and TT in IL21 gene (rs3093390) were found to be 27.6%, 48.3%, 24.1% and 25.2%, 55,5%, 19,3% respectively in HCV infected patients and control group. For IL21R gene (rs2055979) genotype frequencies of CC, CT and TT were 63.8%, 31.4%, 4.8% and 61.4%, 29.7%, 9.0% respectively in HCV infected patients and control group. P values for genotype and allele frequencies were p=0.188, p=0.769 for IL21 gene, and p=0.144, p=0.179 for IL21R gene respectively. CONCLUSION As a result, there is no evidence for an association between IL-21 (rs2055979) and IL-21R (rs3093390) gene polymorphisms with chronic hepatitis C virus in Iranian Patients.
Collapse
Affiliation(s)
- Shahrzad Shoraka
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran,Department of Microbiology and Microbial Biotechnology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, Tehran, Iran
| | - Seyed Reza Mohebbi
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Seyed Masoud Hosseini
- Department of Microbiology and Microbial Biotechnology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, Tehran, Iran
| | - Armin Hosseini Razavi
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Amir Ghaemi
- Department of Virology, Pasteur Institute of Iran, Tehran, Iran
| | - Shabnam Kazemian
- Foodborne and Waterborne Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Rostami-Nejad
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| |
Collapse
|
|
37
|
Fierro N, Gonzalez-Aldaco K, Roman S, Panduro A. The Immune System and Viral Hepatitis. LIVER PATHOPHYSIOLOGY 2017:129-139. [DOI: 10.1016/b978-0-12-804274-8.00009-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
|
|
38
|
Wyles D, Lin J. Clinical Manifestations of Acute and Chronic Hepatitis. Infect Dis (Lond) 2017. [DOI: 10.1016/b978-0-7020-6285-8.00042-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
|
|
39
|
Patel S. In silico analysis of Hepatitis C virus (HCV) polyprotein domains and their comparison with other pathogens and allergens to gain insight on pathogenicity mechanisms. Comput Biol Chem 2016; 65:91-102. [DOI: 10.1016/j.compbiolchem.2016.10.006] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2016] [Revised: 09/12/2016] [Accepted: 10/11/2016] [Indexed: 12/12/2022]
|
|
40
|
Hernández-Bartolomé A, López-Rodríguez R, Borque MJ, González-Moreno L, Real-Martínez Y, García-Buey L, Moreno-Otero R, Sanz-Cameno P. Angiopoietin-2/angiopoietin-1 as non-invasive biomarker of cirrhosis in chronic hepatitis C. World J Gastroenterol 2016; 22:9744-9751. [PMID: 27956798 PMCID: PMC5124979 DOI: 10.3748/wjg.v22.i44.9744] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2016] [Revised: 09/09/2016] [Accepted: 10/10/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate the efficacy of peripheral blood concentrations of angiopoietins (Ang) as cirrhosis biomarkers of chronic hepatitis C (CHC).
METHODS Ang1 and Ang2 serum levels were measured by enzyme-linked immunosorbent assays (ELISA) in samples from 179 cirrhotic and non-cirrhotic CHC patients, classified according to the METAVIR system. Groups were compared by non-parametric Mann-Whitney U test. Subsequently, the association of peripheral concentrations of angiopoietins with the stage of fibrosis was analyzed using Spearman correlation test. Finally, the accuracy, sensitivity and specificity of circulating angiopoietins for cirrhosis diagnosis were determined by the study of the respective area under the curve of receiver operator characteristics (AUC-ROC).
RESULTS Peripheral blood concentrations of Ang1 and Ang2 in CHC patients were significantly related to fibrosis. While Ang1 was decreased in cirrhotic subjects compared to non-cirrhotic (P < 0.0001), Ang2 was significantly increased as CHC progressed to the end stage of liver disease (P < 0.0001). Consequently, Ang2/Ang1 ratio was notably amplified and significantly correlated with fibrosis (P < 0.0001). Interestingly, the individual performance of each angiopoietin for the diagnosis of cirrhosis reached notable AUC-ROC values (above 0.7, both), but the Ang2/Ang1 ratio was much better (AUC-ROC = 0.810) and displayed outstanding values of sensitivity (71%), specificity (84%) and accuracy (82.1%) at the optimal cut-off (10.33). Furthermore, Ang2/Ang1 ratio improved the performance of many other previously described biomarkers or scores of liver cirrhosis in CHC.
CONCLUSION Ang2/Ang1 ratio might constitute a useful tool for monitoring the progression of chronic liver disease towards cirrhosis and play an important role as therapeutic target.
Collapse
|
|
41
|
Chen YC, Wiberg KJ, Hsieh YH, Bansal A, Bolzan P, Guy JA, Maina EN, Cox AL, Thio CL. Favorable Socioeconomic Status and Recreational Polydrug Use Are Linked With Sexual Hepatitis C Virus Transmission Among Human Immunodeficiency Virus-Infected Men Who Have Sex With Men. Open Forum Infect Dis 2016; 3:ofw137. [PMID: 27703998 PMCID: PMC5047398 DOI: 10.1093/ofid/ofw137] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2016] [Accepted: 06/16/2016] [Indexed: 01/03/2023] Open
Abstract
Increasing incident HCV infections were found between 2011-2014 after declining between 2008-2010 among HIV-infected men in a Community Health Center in Baltimore. The reemerging epidemic was associated with sexual transmission and polydrug use among MSM with favorable socioeconomic status. Background. Sexual transmission of hepatitis C virus (HCV) among human immunodeficiency virus (HIV)-infected men who have sex with men (MSM) is an emerging issue. Studies addressing the temporal trends and risk factors associated with incident HCV in HIV-infected MSM in the community-based primary care settings in the United States are scarce. Methods. Using a retrospective cohort study design, HCV incidence, defined as HCV antibody seroconversion, was determined in 1147 HIV-infected men receiving care at Chase Brexton Health Care clinics in Baltimore, Maryland between 2004 and 2014. Multivariate regression analyses were used to identify factors associated with incident HCV. Results. There were 42 incident HCV infections during 5242 person-years (PY) of follow up (incidence rate [IR], 8.01/1000 PY). Thirty-seven (88%) of the incident infections were in MSM, of whom 31 (84%) reported no injection-drug use (IDU). The annual IRs for MSM were 13.1–15.8/1000 PY between 2004 and 2007, decreased to 2.7–6.2/1000 PY between 2008 and 2011, and increased to 10.4/1000 PY and 13.3/1000 PY in 2013 and 2014, respectively. Injection-drug use was strongly associated with incident HCV among all MSM (IR ratio [IRR], 14.15; P = .003); however, among MSM without IDU, entering care between 2010 and 2013 (IRR, 3.32; P = .01), being employed (IRR, 3.14; P = .03), and having a history of ulcerative sexually transmitted infections (IRR, 3.70; P = .009) or of polydrug use (IRR, 5.54; P = .01) independently predicted incident HCV. Conclusions. In this cohort of HIV-infected men, a re-emerging HCV epidemic was observed from 2011 to 2014 among MSM. In addition to IDU, high-risk sexual behaviors, favorable socioeconomic status, and polydrug use fueled this increase in HCV infections.
Collapse
Affiliation(s)
- Yun-Chi Chen
- Laboratory of Biomedical Sciences and Epidemiology and Immune Knowledge of Infectious Diseases; Department of Biology; M.S. in Biology Program, Morgan State University
| | - Kjell J Wiberg
- Chase Brexton Health Care; Division of Infectious Diseases, Department of Medicine, Sinai Hospital; Department of Medicine
| | - Yu-Hsiang Hsieh
- Department of Emergency Medicine, Johns Hopkins University , Baltimore, Maryland
| | - Arun Bansal
- Laboratory of Biomedical Sciences and Epidemiology and Immune Knowledge of Infectious Diseases
| | - Philipe Bolzan
- Laboratory of Biomedical Sciences and Epidemiology and Immune Knowledge of Infectious Diseases
| | - Janelle A Guy
- Laboratory of Biomedical Sciences and Epidemiology and Immune Knowledge of Infectious Diseases
| | - Erastus N Maina
- Laboratory of Biomedical Sciences and Epidemiology and Immune Knowledge of Infectious Diseases; M.S. in Biology Program, Morgan State University
| | | | | |
Collapse
|
|
42
|
Chadha S, Sharma U, Chaudhary A, Prakash C, Gupta S, Venkatesh S. Molecular epidemiological analysis of three hepatitis C virus outbreaks in Jammu and Kashmir State, India. J Med Microbiol 2016; 65:804-813. [PMID: 27357565 DOI: 10.1099/jmm.0.000284] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Outbreaks of hepatitis C virus (HCV) infection are associated with unsafe injection practices, intravenous drug abuse and other exposure to blood and body fluids. We report here three outbreaks of HCV infection from Jammu and Kashmir (J&K) State, India, which occurred over a period of 3 years and in which molecular epidemiological investigations identified a presumptive common source of infection, most likely a single healthcare venue. Representative blood samples collected from cases of hepatitis C were sent to the National Centre for Disease Control (NCDC) for molecular characterization. These samples were positive by HCV ELISA. Subsequently, specimens were also tested for the presence of HCV RNA by RT-PCR. Sequencing was carried out for all positive samples. A total of 812 cases were laboratory confirmed by HCV ELISA; a total of 115 samples were sent to the NCDC for RT-PCR, and 77 were positive. Subtype 3a of HCV was found in all samples from Anantnag (February 2013); and for subtype 3b, in all samples from Srinagar (May 2015). Subtypes 3a and 3g were identified from two samples from the Kulgam outbreak (July 2014). A detailed epidemiological investigation should be conducted whenever a cluster of HCV cases is revealed, as this potentially allows for the identification of larger outbreaks. Epidemiological investigations of outbreaks should be further supported by inclusion of molecular tests. Efforts to limit therapeutic injections to only those cases having strong medical/surgical indications and to restrict the use of non-sterile needles are essential to prevent transmission of HCV.
Collapse
Affiliation(s)
- Sanjim Chadha
- Division of Biotechnology and Molecular Diagnostics, National Centre for Disease Control, Directorate General of Health Services, Ministry of Health & Family Welfare, Government of India, 22-Sham Nath Marg, Delhi 110054, India
| | - Uma Sharma
- Division of Biotechnology and Molecular Diagnostics, National Centre for Disease Control, Directorate General of Health Services, Ministry of Health & Family Welfare, Government of India, 22-Sham Nath Marg, Delhi 110054, India
| | - Artee Chaudhary
- Division of Biotechnology and Molecular Diagnostics, National Centre for Disease Control, Directorate General of Health Services, Ministry of Health & Family Welfare, Government of India, 22-Sham Nath Marg, Delhi 110054, India
| | - Charu Prakash
- Division of Biotechnology and Molecular Diagnostics, National Centre for Disease Control, Directorate General of Health Services, Ministry of Health & Family Welfare, Government of India, 22-Sham Nath Marg, Delhi 110054, India
| | - Sunil Gupta
- Division of Biotechnology and Molecular Diagnostics, National Centre for Disease Control, Directorate General of Health Services, Ministry of Health & Family Welfare, Government of India, 22-Sham Nath Marg, Delhi 110054, India
| | - S Venkatesh
- Division of Biotechnology and Molecular Diagnostics, National Centre for Disease Control, Directorate General of Health Services, Ministry of Health & Family Welfare, Government of India, 22-Sham Nath Marg, Delhi 110054, India
| |
Collapse
|
|
43
|
Corral-Jara KF, Trujillo-Ochoa JL, Realpe M, Panduro A, Roman S, Fierro NA. Rethinking the immune properties of bilirubin in viral hepatitis: from bench to bedside. Clin Transl Immunology 2015; 4:e54. [PMID: 26719800 PMCID: PMC4685441 DOI: 10.1038/cti.2015.37] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2015] [Revised: 11/04/2015] [Accepted: 11/15/2015] [Indexed: 02/07/2023] Open
Abstract
Communication between the immune system and metabolic components can be exemplified by the process of heme catabolism. The immunomodulatory functions of the enzymes, substrates and active products related to catabolism of the heme group have been extensively studied. Bilirubin (BR), the final breakdown product of heme, is primarily considered to be a toxic waste product but has recently been considered to be an immunomodulatory metabolite. Through mechanisms that include intracellular signaling and transcriptional control, BR affects those immune cell functions that regulate cell proliferation, differentiation and apoptosis. During the pathogenesis of viral hepatitis, the heme degradation pathway is disrupted, resulting in changes to normal BR concentrations. These alterations have been previously studied mainly as a consequence of the infection. However, little is known about the potential immunomodulatory role played by BR in the development of infectious hepatocellular diseases. Differences in BR levels in the context of viral hepatitis are likely to provide important insights into the metabolite-mediated mechanisms controlling the immune responses underlying both the long-term persistence of hepatitis C virus (HCV) infection and the resolution of hepatitis A virus (HAV) infection during the acute phase. In this review, the cross-talk between heme catabolism and immune function is described in detail. Special emphasis is given to discoveries that hold promise for identifying immunologic features of metabolic products in the resolution of viral diseases.
Collapse
Affiliation(s)
- Karla F Corral-Jara
- Unidad de Inmunovirología, Servicio de Biología Molecular en Medicina, Hospital Civil de Guadalajara 'Fray Antonio Alcalde' , Guadalajara, Mexico ; Departamento de Biología Molecular, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara , Guadalajara, Mexico
| | - Jorge L Trujillo-Ochoa
- Unidad de Inmunovirología, Servicio de Biología Molecular en Medicina, Hospital Civil de Guadalajara 'Fray Antonio Alcalde' , Guadalajara, Mexico ; Departamento de Fisiologia, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara , Guadalajara, Mexico
| | - Mauricio Realpe
- Departamento de Medicina Veterinaria, Centro Universitario de Ciencias Biológicas y Agropecuarias, Universidad de Guadalajara , Guadalajara, Mexico
| | - Arturo Panduro
- Servicio de Biología Molecular en Medicina, Hospital Civil of Guadalajara 'Fray Antonio Alcalde' , Guadalajara, Mexico ; Departamento de Clínicas Médicas, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara , Guadalajara, Mexico
| | - Sonia Roman
- Departamento de Biología Molecular, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara , Guadalajara, Mexico ; Servicio de Biología Molecular en Medicina, Hospital Civil of Guadalajara 'Fray Antonio Alcalde' , Guadalajara, Mexico
| | - Nora A Fierro
- Unidad de Inmunovirología, Servicio de Biología Molecular en Medicina, Hospital Civil de Guadalajara 'Fray Antonio Alcalde' , Guadalajara, Mexico ; Departamento de Fisiologia, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara , Guadalajara, Mexico
| |
Collapse
|
|
44
|
Al-Anazi MR, Matou-Nasri S, Abdo AA, Sanai FM, Khan MQ, Albenmousa A, Al-Ashgar HI, Khalaf NZ, Al-Ahdal MN, Al-Qahtani AA. Variations in DEPDC5 gene and its association with chronic hepatitis C virus infection in Saudi Arabia. BMC Infect Dis 2014; 14:632. [PMID: 25551790 PMCID: PMC4311515 DOI: 10.1186/s12879-014-0632-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2014] [Accepted: 11/13/2014] [Indexed: 02/08/2023] Open
Abstract
Background Variations at DEPDC5 gene have been recently reported as genetic markers associated with hepatocellular carcinoma (HCC) progression in chronic HCV-infected patients. This study was conducted to assess the association of DEPDC5 variants with advanced liver cirrhosis and HCC development among chronic HCV-infected patients in Saudi Arabian population. Methods Six-hundred and one HCV-infected patients were genotyped for DEPDC5 polymorphisms (rs1012068 and rs5998152), in comparison with 592 non-infected healthy control subjects. The allelic frequency and genotype distribution of both DEPDC5 polymorphisms were determined followed by haplotype frequency estimation and multiple logistic regression analysis. Results The frequency of the risk alleles of both rs1012068 and rs5998152 was shown to be more in healthy control subjects than in patients (p = 0.0001, OR = 0.704, CI = 0.591-0.839; p = 0.002, OR = 0.761, CI = 0. 0.639-0.907, respectively). Also, our results revealed that GT for SNP rs1012068 (OR =1.715; 95% CI 1.132-2.597; p = 0.0104) and CT for SNP rs5998152 (OR = 1.932; 95% CI 1.276-2.925; p = 0.0017) showed significant association with development of cirrhosis compared with the GG and CC genotypes, respectively. The data also revealed that subjects with the T allele of both SNPs appeared to have a lower susceptibility to HCV-related cirrhosis/HCC than those with the G allele of rs1012068 (p = 0.038, OR = 1.353, 95 % CI 1.017-1.800) and C allele of rs5998152 (p = 0.043, OR = 1.342, 95 % CI 1.010-1.784). Haplotype analysis showed that a combination of T-T alleles of rs1012068 and rs5998152 was significantly associated with liver cirrhosis (frequency = 71.3% and p = 0.027) and with cirrhosis/HCC (frequency = 71.4% and P = 0.045). Also, multiple logistic regression analysis showed that rs5998152 (OR = 2.844, 95% CI 1.333-6.069 and p = 0.007), rs1012068 (OR = 2.793, 95% CI 1.316-5.928 and p = 0.010), age (OR = 1.029, 95% CI 1.001-1.057 and p = 0.041) and HCV genotypes (OR = 0.247, 95% CI 0.097-0.630 and p = 0.003) were independently associated with chronicity of HCV infection. Conclusion Genetic variations in DEPDC5 gene region may influence HCV-associated liver cirrhosis and/or HCC development.
Collapse
|
|
45
|
Al Olaby RR, Cocquerel L, Zemla A, Saas L, Dubuisson J, Vielmetter J, Marcotrigiano J, Khan AG, Catalan FV, Perryman AL, Freundlich JS, Forli S, Levy S, Balhorn R, Azzazy HM. Identification of a novel drug lead that inhibits HCV infection and cell-to-cell transmission by targeting the HCV E2 glycoprotein. PLoS One 2014; 9:e111333. [PMID: 25357246 PMCID: PMC4214736 DOI: 10.1371/journal.pone.0111333] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2014] [Accepted: 09/23/2014] [Indexed: 12/17/2022] Open
Abstract
Hepatitis C Virus (HCV) infects 200 million individuals worldwide. Although several FDA approved drugs targeting the HCV serine protease and polymerase have shown promising results, there is a need for better drugs that are effective in treating a broader range of HCV genotypes and subtypes without being used in combination with interferon and/or ribavirin. Recently, two crystal structures of the core of the HCV E2 protein (E2c) have been determined, providing structural information that can now be used to target the E2 protein and develop drugs that disrupt the early stages of HCV infection by blocking E2’s interaction with different host factors. Using the E2c structure as a template, we have created a structural model of the E2 protein core (residues 421–645) that contains the three amino acid segments that are not present in either structure. Computational docking of a diverse library of 1,715 small molecules to this model led to the identification of a set of 34 ligands predicted to bind near conserved amino acid residues involved in the HCV E2: CD81 interaction. Surface plasmon resonance detection was used to screen the ligand set for binding to recombinant E2 protein, and the best binders were subsequently tested to identify compounds that inhibit the infection of Huh-7 cells by HCV. One compound, 281816, blocked E2 binding to CD81 and inhibited HCV infection in a genotype-independent manner with IC50’s ranging from 2.2 µM to 4.6 µM. 281816 blocked the early and late steps of cell-free HCV entry and also abrogated the cell-to-cell transmission of HCV. Collectively the results obtained with this new structural model of E2c suggest the development of small molecule inhibitors such as 281816 that target E2 and disrupt its interaction with CD81 may provide a new paradigm for HCV treatment.
Collapse
Affiliation(s)
- Reem R. Al Olaby
- Department of Chemistry, The American University in Cairo, New Cairo, Egypt
| | - Laurence Cocquerel
- Center for Infection and Immunity of Lille, CNRS-UMR8204/Inserm-U1019, Pasteur Institute of Lille, University of Lille North of France, Lille, France
| | - Adam Zemla
- Pathogen Bioinformatics, Lawrence Livermore National Laboratory, Livermore, CA, United States of America
| | - Laure Saas
- Center for Infection and Immunity of Lille, CNRS-UMR8204/Inserm-U1019, Pasteur Institute of Lille, University of Lille North of France, Lille, France
| | - Jean Dubuisson
- Center for Infection and Immunity of Lille, CNRS-UMR8204/Inserm-U1019, Pasteur Institute of Lille, University of Lille North of France, Lille, France
| | - Jost Vielmetter
- Protein Expression Center, Beckman Institute, California Institute of Technology, Pasadena, CA, United States of America
| | - Joseph Marcotrigiano
- Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ, United States of America
| | - Abdul Ghafoor Khan
- Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ, United States of America
| | - Felipe Vences Catalan
- Department of Medicine, Stanford University Medical Center, Stanford, CA, United States of America
| | - Alexander L. Perryman
- Department of Medicine, Division of Infectious Diseases, Center for Emerging & Re-emerging Pathogens, Rutgers University-New Jersey Medical School, Newark, NJ, United States of America
| | - Joel S. Freundlich
- Department of Medicine, Division of Infectious Diseases, Center for Emerging & Re-emerging Pathogens, Rutgers University-New Jersey Medical School, Newark, NJ, United States of America
- Department of Pharmacology and Physiology, Rutgers University-New Jersey Medical School, Newark, NJ, United States of America
| | - Stefano Forli
- Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, United States of America
| | - Shoshana Levy
- Department of Medicine, Stanford University Medical Center, Stanford, CA, United States of America
| | - Rod Balhorn
- Department of Applied Science, University of California Davis, Davis, CA, United States of America
- * E-mail:
| | - Hassan M. Azzazy
- Department of Chemistry, The American University in Cairo, New Cairo, Egypt
| |
Collapse
|
|
46
|
Sagnelli E, Santantonio T, Coppola N, Fasano M, Pisaturo M, Sagnelli C. Acute hepatitis C: clinical and laboratory diagnosis, course of the disease, treatment. Infection 2014; 42:601-610. [PMID: 24619833 DOI: 10.1007/s15010-014-0608-2] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2013] [Accepted: 02/24/2014] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Acute hepatitis C (AHC) is asymptomatic in about 70-80 % of cases and, therefore, is usually undiagnosed. Although the clinical course is typically mild, AHC has a high rate of transition to chronicity. MATERIAL AND METHODS We evaluated the literature data concerning risk factors for HCV transmission, diagnosis, natural history, and antiviral treatment of AHC. RESULTS Although new methods have been developed, anti-HCV seroconversion remains the gold standard for the diagnosis of AHC. This phenomenon, however, is identifiable in less than half of cases in the everyday clinical practice, since most AHC patients do not know their previous anti-HCV/HCV-RNA status. An early short-term interferon treatment in AHC patients prevents progression to chronicity in most of treated patients. CONCLUSION The literature data give evidence of the clinical relevance of an early diagnosis of AHC for an early short-term interferon treatment. There is also the suggestion to use newly developed laboratory methods to distinguish AHC from an acute exacerbation of a chronic HCV infection.
Collapse
Affiliation(s)
- E Sagnelli
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, Second University of Naples, via L. Armanni, No. 3, 80135, Naples, Italy,
| | | | | | | | | | | |
Collapse
|
|
47
|
Santantonio T, Fasano M, Sagnelli E, Tundo P, Babudieri S, Fabris P, Toti M, Di Perri G, Marino N, Pizzigallo E, Angarano G. Acute hepatitis C: a 24-week course of pegylated interferon α-2b versus a 12-week course of pegylated interferon α-2b alone or with ribavirin. Hepatology 2014; 59:2101-2109. [PMID: 24442928 DOI: 10.1002/hep.26991] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2013] [Revised: 11/19/2013] [Accepted: 12/23/2013] [Indexed: 01/01/2023]
Abstract
UNLABELLED Therapy of acute hepatitis C (AHC) has not yet been standardized and several issues are still unresolved. This open, randomized, multicenter trial aimed to assess the efficacy and safety of a 24-week course of pegylated IFN (Peg-IFN) alpha-2b versus a 12-week course of Peg-IFN alpha-2b alone or with ribavirin (RBV) in AHC patients. One hundred and thirty HCV acutely infected patients who did not spontaneously resolve by week 12 after onset were consecutively enrolled and randomized to receive Peg-IFN alpha-2b monotherapy (1.5 μg/kg/week) for 24 or 12 weeks (arm 1, n = 44 and arm 2, n = 43, respectively) or in combination with RBV (10.6 mg/kg/day) for 12 weeks (arm 3, n = 43). The primary endpoint was undetectable HCV RNA at 6-month posttreatment follow-up (sustained virological response; SVR). All patients were followed for 48 weeks after therapy cessation. HCV RNA levels were determined by real-time polymerase chain reaction (limit of detection: 15 IU/mL) at the central laboratory at baseline, week 4, end of treatment, and 6 and 12 months posttreatment. Using an intent-to-treat analysis, overall SVR rate was 71.5%. In particular, an SVR was achieved in 31 of 44 (70.5%), 31 of 43 (72.1%), and 31 of 43 (72.1%) patients in arms 1, 2, and 3, respectively (P = 0.898). Sixteen patients (12.3%) prematurely discontinued therapy or were lost to follow-up; thus, sustained response rates with per-protocol analysis were 81.6%, 81.6%, and 81.6% for patients in arms 1, 2, and 3 respectively. With multivariate analysis, virologic response at week 4 of treatment was an independent predictor of SVR. Peg-IFN alpha-2b was well tolerated. CONCLUSION Peg-IFN alpha-2b induces a high SVR in chronically evolving AHC patients. Response rates were not influenced by combination therapy or treatment duration.
Collapse
|
|
48
|
Méndez-Sánchez N, Ridruejo E, Alves de Mattos A, Chávez-Tapia NC, Zapata R, Paraná R, Mastai R, Strauss E, Guevara-Casallas LG, Daruich J, Gadano A, Parise ER, Uribe M, Aguilar-Olivos NE, Dagher L, Ferraz-Neto BH, Valdés-Sánchez M, Sánchez-Avila JF. Latin American Association for the Study of the Liver (LAASL) clinical practice guidelines: management of hepatocellular carcinoma. Ann Hepatol 2014; 13 Suppl 1:S4-S40. [PMID: 24998696 DOI: 10.1016/s1665-2681(19)30920-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2025]
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world and the third most common cause of cancer death, and accounts for 5.6% of all cancers. Nearly 82% of the approximately 550,000 liver cancer deaths each year occur in Asia. In some regions, cancer-related death from HCC is second only to lung cancer. The incidence and mortality of HCC are increasing in America countries as a result of an ageing cohort infected with chronic hepatitis C, and are expected to continue to rise as a consequence of the obesity epidemic. Clinical care and survival for patients with HCC has advanced considerably during the last two decades, thanks to improvements in patient stratification, an enhanced understanding of the pathophysiology of the disease, and because of developments in diagnostic procedures and the introduction of novel therapies and strategies in prevention. Nevertheless, HCC remains the third most common cause of cancer-related deaths worldwide. These LAASL recommendations on treatment of hepatocellular carcinoma are intended to assist physicians and other healthcare providers, as well as patients and other interested individuals, in the clinical decision-making process by describing the optimal management of patients with liver cancer.
Collapse
Affiliation(s)
| | - Ezequiel Ridruejo
- Hepatology Section, Department of Medicine. Centro de Educación Médica e Investigaciones Clínicas Norberto Quirno "CEMIC". Ciudad Autónoma de Buenos Aires, Argentina; Hepatology and Liver Transplant Unit. Hospital Universitario Austral, Pilar, Argentina
| | | | | | - Rodrigo Zapata
- Hepatology and Liver Transplantation Unit. University of Chile School of Medicine, German Clinic. Santiago, Chile
| | - Raymundo Paraná
- Associate Professor of School of Medicine - Federal University of Bahia Head of the Gastro-Hepatologist Unit of the University Bahia University Hospital
| | - Ricardo Mastai
- Transplantation Unit. German Hospital.Buenos Aires, Argentina
| | - Edna Strauss
- Clinical hepatologist of Hospital do Coraçao - São Paulo - Brazil. Professor of the Post Graduate Course in the Department of Pathology at the School of Medicine, University of São Paulo
| | | | - Jorge Daruich
- Hepatology Department, Clinical Hospital San Martín. University of Buenos Aires Buenos Aires, Argentina
| | - Adrian Gadano
- Section of Hepatology, Italian Hospital of Buenos Aires. Buenos Aires, Argentina
| | - Edison Roberto Parise
- Professor Associado da Disciplina de Gastroenterologia da Universidade Federal de São Paulo, Presidente Eleito da Sociedade Brasileira de Hepatologia
| | - Misael Uribe
- Digestive Diseases and Obesity Clinic, Medica Sur Clinic Foundation. México City, Mexico
| | - Nancy E Aguilar-Olivos
- Digestive Diseases and Obesity Clinic, Medica Sur Clinic Foundation. México City, Mexico
| | - Lucy Dagher
- Consultant Hepatologist. Metropolitan Policlinic- Caracas- Venezuela
| | - Ben-Hur Ferraz-Neto
- Director of Liver Institute - Beneficencia Portuguesa de São Paulo. Chief of Liver Transplantation Team
| | - Martha Valdés-Sánchez
- Department of Pediatric Oncology National Medical Center "Siglo XXI". Mexico City, Mexico
| | - Juan F Sánchez-Avila
- Hepatology and Liver Transplantation Department National Institute of Nutrition and Medical Sciences "Salvador Zubirán" Mexico City, Mexico
| |
Collapse
|
|
49
|
Abstract
A 42-year-old woman developed epigastric abdominal pain and acutely elevated serum transaminase levels during a course of chemotherapy for breast cancer. Serum antibodies to hepatitis A, B and C were not identified initially, but subsequently a high hepatitis C viral load was detected. Ultrasonic imaging of the liver was normal. Serum transaminase elevations resolved within 2 months, and, after 6 months without therapy, the hepatitis C viral load became undetectable.
Collapse
Affiliation(s)
- Allison Venner
- Division of Gastroenterology and Hepatology, 1 University of New Mexico, MSC10-5550, Albuquerque, NM, 87131, USA,
| | | |
Collapse
|
|
50
|
Beinhardt S, Payer BA, Datz C, Strasser M, Maieron A, Dorn L, Grilnberger-Franz E, Dulic-Lakovic E, Stauber R, Laferl H, Aberle JH, Holzmann H, Krall C, Vogel W, Ferenci P, Hofer H. A diagnostic score for the prediction of spontaneous resolution of acute hepatitis C virus infection. J Hepatol 2013; 59:972-977. [PMID: 23850880 DOI: 10.1016/j.jhep.2013.06.028] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2013] [Revised: 05/30/2013] [Accepted: 06/26/2013] [Indexed: 01/16/2023]
Abstract
BACKGROUND & AIMS IL28B polymorphisms, jaundice, decline in HCV-RNA, IP-10, and gender have been proposed to be indicative of spontaneous clearance of acute hepatitis C virus infection. The aim of this study was to define a score enabling the discrimination of patients with spontaneous clearance of HCV from those with development of viral persistence and need for early antiviral treatment. METHODS 136 patients (74 male; 35 ± 15 years) were analyzed. From variables predictive of spontaneous clearance, calculated by univariate analysis, three scores were built. Analogous cut-offs were evaluated by computing area under the receiver operating characteristic curves. Candidate variables and cut-offs were: (I) presence of IL28B C/C (p=0.027), (II) age (p=0.031; cut-off: 35 years), (III) peak-bilirubin (p=0.018; cut-off: 6 mg/dl), (IV) HCV-RNA decline within 4 weeks (p<0.001;cut-off: >2.5 log), (V) serum IP-10 (p=0.003; cut-off: 546 pg/ml), (VI) presence of CD4(+) Th1 cells (p=0.024). Each variable was allocated to 0 or 1 point, an HCV-RNA decline of ≥ 1 log 10 but <2.5 log 10 to 1 point, a decline of ≥ 2.5 log 10 to 2 points. Three scores were evaluated (Score 1: I-IV; Score 2: I-V; Score 3: I-VI). RESULTS A cut-off of ≥ 3 points out of 5 in Score 1 (AUROC: 0.82; DeLong 95% CI: 0.76-0.93) predicted spontaneous clearance with a sensitivity of 71% (95% CI: 0.53-0.86) and specificity of 87% (95% CI: 0.73-0.95). PPV and NPV were 79% and 82%. Corresponding findings for Score 2 including IP-10 (AUROC: 0.93; DeLong 95% CI: 0.86-0.93) at a cut-off of ≥ 4 were: sensitivity 81%, specificity 95% (PPV: 100%; NPV: 77%). A cut-off of ≥ 5 in Score 3 (AUROC: 0.98; DeLong 95% CI: 0.95-1.0) predicted spontaneous resolution with a sensitivity of 75% and specificity of 100% (PPV: 100%; NPV: 88%). CONCLUSIONS The scores enable a reliable discrimination between AHC-patients with high potential for spontaneous clearance from candidates for early therapeutic intervention due to marginal chance of spontaneous resolution.
Collapse
Affiliation(s)
- Sandra Beinhardt
- Internal Medicine III, Department of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|