The hepatitis C virus (HCV), an obligatory intracellular pathogen, highly depends on its host cells to propagate successfully. The HCV life cycle can be simply divided into several stages including viral entry, protein translation, RNA replication, viral assembly and release. Hundreds of cellular factors involved in the HCV life cycle have been identified over more than thirty years of research. Characterization of these cellular factors has provided extensive insight into HCV replication strategies. Some of these cellular factors are targets for anti-HCV therapies. In this review, we summarize the well-characterized and recently identified cellular factors functioning at each stage of the HCV life cycle.

Model of hepatitis C virus particles (lipo-viral particles) secreted from cells. A: Most of the lipo-viral particles (LPV)’s membrane is a lipid monolayer. A bilayer-containing region is where the viral envelope proteins (i.e., E1 and E2) are inserted. Viral envelope proteins may also exist in the phospholipid monolayer membrane. Though the precise structure has not yet been determined, LVPs are believed to have multiple copies of Apo-E and less Apo-A1 molecules but only one Apo-B100 molecule (left). Some LPVs may not have Apo-B (right). Within the phospholipid monolayer, there are the core proteins wrapping the viral RNA genome and neutral lipids (e.g., cholesterol esters and triglycerides); B: Serum lipoproteins are possibly associated with hepatitis C virus particles in different ways. HCV: Hepatitis C virus.
Model of cell-free virus entry into hepatocytes. Hepatitis C virus (HCV) lipo-viral particles (LPVs) may be captured by DC-SIGN on the dendritic cells or L-SIGN on the endothelium in the sinusoidal space. After transfer to Space of Disse, HCV LPVs could attach to the hepatocytes through interacting with highly sulfated heparan sulfate proteoglycans, low-density lipoprotein receptor and scavenger receptor class B type 1 (1). This attachment allows the engagement of LPVs to cluster of differentiation 81 (CD81) and then induces the epidermal growth factor receptor receptor signaling (2). Lateral diffusion of the CD81–HCV complexes results in the association of CD81–HCV with Claudin-1 (3) and then OCLIN (4). Formation of the HCV–CD81–CLDN1–OCLIN complex allows viral particles internalized through clathrin-dependent endocytosis (5). Endosomal acidification induces the fusion of viral particles possibly through E1 and leads to the release of the viral genomic RNA into cytosol (6). HSPGs: Heparan sulfate proteoglycans; HCV: Hepatitis C virus; EGFR: Epidermal growth factor receptor; LDLR: Low-density lipoprotein receptor.
Hepatitis C virus protein translation. A: Translation of hepatitis C virus (HCV) genomic RNA is regulated by the internal ribosome entry site in the 5’-untranslated region (5’UTR) along with a short segment of the core gene sequence, the cis-acting replication element in the NS5B coding region and by the entire 3’UTR. Binding sites for eIF3 and 40S were marked. The start and stop codons for protein translation are marked by black squares, while two recognition sites on the 5’UTR for miR122 are marked by black rectangles; B: Polyprotein is co- and post-translationally cleaved by host or viral proteases to yield the structural proteins (core, E1 and E2) and the nonstructural proteins (p7, NS2, NS3, NS4A, NS4B, NS5A and NS5B proteins). Core, E1 and E2 are processed by cellular signal peptidase (filled arrowhead). Mature core protein will be generated after further cleavage by signal peptide peptidase (empty arrowhead)[317]. The NS2/NS3 junction site is cleaved by the NS2–NS3 auto-protease[318] (empty arrow), and the remaining nonstructural proteins are processed by the NS3/4A proteinase[319] (filled arrow); C: All of the HCV proteins are associated with endoplasmic reticulum directly or indirectly[320]; D: Then, NS3, NS4A, NS4B, NS5A and NS5B proteins will form the replication complex. Core and NS5A proteins will be transferred to lipid droplets, while E1 and E2 proteins will stay in the assembly sites. IRES: Internal ribosome entry site; 5’UTR: 5’-untranslated region.

A proposed model for hepatitis C virus assembly. Lipid droplets (LDs) are surrounded by endoplasmic reticulum (ER)[321]. LDs with a hepatitis C virus (HCV) core and NS5A proteins are close to replication sites [double membrane vesicle (DMV)] and assembly sites. HCV genomic RNA synthesized by the replication complex (NS3–NS5B proteins) in the DMVs will be transferred by NS5A and NS3-4A proteins and encapsidated by the core proteins to form the nucleocapsid. Then, the HCV nucleocapsid will interact with glycoproteins E1/E2 in the assembly sites and bud into the ER lumen. Both Apo-B-dependent and -independent mechanisms are possibly involved in HCV particle assembly. One model shows the production of a fused form of HCV with very-low-density lipoproteins. Another model shows the budding of HCV particles with several apolipoproteins but not Apo-B. Nascent viral particles may be further lipidated by luminal lipoproteins and incorporated with exchangeable apolipoproteins. ER: Endoplasmic reticulum.

More than twenty years of study has provided a better understanding of hepatitis C virus (HCV) life cycle, including the general properties of viral RNA and proteins. This effort facilitates the development of sensitive diagnostic tools and effective antiviral treatments. At present, serologic screening test is recommended to perform on individuals in the high risk groups and nucleic acid tests are recommended to confirm the active HCV infections. Quantization and genotyping of HCV RNAs are important to determine the optimal duration of anti-viral therapy and predict the likelihood of response. In the early 2000s, pegylated interferon plus ribavirin became the standard anti-HCV treatment. However, this therapy is not ideal. To 2014, boceprevir, telaprevir, simeprevir, sofosbuvir and Harvoni are approved by Food and Drug Administration for the treat of HCV infections. It is likely that the new all-oral, interferon-free, pan-genotyping anti-HCV therapy will be available within the next few years. Majority of HCV infections will be cured by these anti-viral treatments. However, not all patients are expected to be cured due to viral resistance and the high cost of antiviral treatments. Thus, an efficient prophylactic vaccine will be the next challenge in the fight against HCV infection.

J Biol Chem. 2006 Mar 31;281(13):8305-7. Epub 2005 Dec 30.

Viral agents of infectious disease such as human immunodeficiency virus (HIV),2 influenza virus, and hepatitis C virus (HCV) continue to pose daunting public health challenges. Substantial information is known about the multiplication cycles, the means of transmission, and the diseases caused by these three viruses, all of which are human pathogens that possess RNA genomes (1). Efforts to understand their viral multiplication schemes at the molecular level and to elucidate the interactions that occur between viral and cellular gene products that together determine the host’s susceptibility to infection and disease have led to significant new insights about HIV, influenza, and HCV viruses. The first two minireviews in this three-part series concern HIV and influenza virus. They focus on the genetic and biochemical aspects of two viral proteins, the Vif protein of HIV (2) and the M2 protein of influenza virus (3), and the functional roles that they play during establishment of productive viral infections. The third minireview focuses on the structure and function of the viral proteins involved in the replication of HCV RNA (4).

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Overview

These are the first guidelines dealing with hepatitis C treatment produced by the World Health Organization (WHO) and complement existing guidance on the prevention of transmission of bloodborne viruses, including HCV. They are intended for policy-makers, government officials, and others working in low- and middleincome countries who are developing programmes for the screening, care and treatment of persons with HCV infection.

These guidelines serve as a framework that can allow the expansion of clinical services to patients with HCV infection, as they provide key recommendations in these areas and discuss considerations for implementation. The guidelines are also intended for health-care providers who care for persons with HCV infection in low- and middle-countries and provide them guidance in the management of patients infected with HCV.

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World J Gastroenterol. 2012 Apr 14;18(14):1642-51.

Abstract
AIM: To investigate the association between hepatitis C infection and type 2 diabetes mellitus.

METHODS: Observational studies assessing the relationship between hepatitis C infection and type 2 diabetes mellitus were identified via electronic and hand searches. Studies published between 1988 to March 2011 were screened, according to the inclusion criteria set for the present analysis. Authors performed separate analyses for the comparisons between hepatitis C virus (HCV) infected and not infected, and HCV infected and hepatitis B virus infected. The included studies were further subgrouped according to the study design. Heterogenity was assessed using I(2) statistics. The summary odds ratios with their corresponding 95% CIs were calculated based on a random-effects model. The included studies were subgrouped according to the study design. To assess any factor that could potentially affect the outcome, results were further stratified by age group (proportion of ≥ 40 years), gender (proportion of male gender), body mass index (BMI) (proportion of BMI ≥ 27), and family history of diabetes (i.e., self reported). For stability of results, a sensitivity analysis was conducted including only prospective studies.

RESULTS: Combining the electronic database and hand searches, a total of 35 observational studies (in 31 articles) were identified for the final analysis. Based on random-effects model, 17 studies (n = 286 084) compared hepatitis C-infected patients with those who were uninfected [summary odds ratio (OR): 1.68, 95% CI: 1.15-2.45]. Of these 17 studies, 7 were both a cross-sectional design (41.2%) and cohort design (41.2%), while 3 were case-control studies (17.6%). Nineteen studies (n = 51 156) compared hepatitis C-infected participants with hepatitis B-infected (summary OR: 1.92, 95% CI: 1.41-2.62). Of these 19 studies, 4 (21.1%), 6 (31.6%) and 9 (47.4%) were cross-sectional, cohort and case-control studies, respectively. A sensitivity analysis with 3 prospective studies indicated that hepatitis C-infected patients had a higher risk of developing type 2 diabetes compared with uninfected controls (summary odds ratio: 1.41, 95% CI: 1.17-1.7; I(2) = 0%). Among hepatitis C-infected patients, male patients (OR: 1.26, 95% CI: 1.03-1.54) with age over 40 years (summary OR: 7.39, 95% CI: 3.82-9.38) had an increased frequency of type 2 diabetes. Some caution must be taken in the interpretation of these results because there may be unmeasured confounding factors which may introduce bias.

CONCLUSION: The findings support the association between hepatitis C infection and type 2 diabetes mellitus. The direction of association remains to be determined, however. Prospective studies with adequate sample sizes are recommended.

Klimik Dergisi 2009; 22(2): 38-43.

Hepatit C, kronik karaciğer hastalığı, siroz ve hepatosellüler karsinomaya yol açabilen önemli bir infeksiyon hastalığıdır. Dünyada 130-170 milyon kişinin hepatit C virusu (HCV) ile infekte olduğu tahmin edilmektedir. Hepatit C prevalansı ve bulaşma yolları ülkeler ve bölgeler arasında değişkenlik gösterir. Ülkemiz dünya haritasında prevalansı %1-1.9 arasında olan dilim içinde yer alır. Gelecekte, HCV’ye bağlı kronik karaciğer hastalığı gibi komplikasyonların, toplumu ne düzeyde etkileyeceğinin belirlenebilmesi için HCV insidansındaki değişimlerin bilinmesi ve izlenmesi gerekir, bunun için de en uygunu yaşa spesifik prevalans oranlarının değerlendirilmesidir. Ülkemizde kan transfüzyonu, güvenli olmayan injeksiyon ama en önemlisi gerek hastane içinde gerekse hastane dışında uygulanan tıbbi işlemler sırasında temizlik ve dezenfeksiyona özen gösterilmemesi HCV’nin yayılımındaki en önemli unsurlardır. Ülkemizde şu andaki HCV’ye bağlı kronik karaciğer hastalığı sorunu, geçmiş yıllardaki yaygın bulaşmaların sonucudur ve oldukça önemli boyuttadır; ancak gerekli önlemler alınmazsa gelecekte de sorun olmaya devam edecektir.

HEPATOLOGY 2009; 49: 1335-74

Intended for use by physicians, these recommendations suggest preferred approaches to the diagnostic, therapeutic and preventive aspects of care. They are intended to be flexible, in contrast to standards of care, which are inflexible policies to be followed in every case. Specific recommendations are based on relevant published information. To more fully characterize the quality of evidence supporting recommendations, the Practice Guidelines Committee of the AASLD requires a Class (reflecting benefit versus risk) and Level (assessing strength or certainty) of Evidence to be assigned and reported with each recommendation (Table 1, adapted from the American College of Cardiology and the American Heart association Practice Guidelines)

Hepatitis C 2004 Guideline (PDF)