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Hepatitis C Virus: Pathogenetic Mechanisms, Residual Problems after Cure and Hopes for Elimination

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (25 March 2024) | Viewed by 6216

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Special Issue Editor

Prof. Dr. Mario Mondelli

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Guest Editor

Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy
Interests: viral hepatitis

Special Issue Information

Dear Colleagues,

Hepatitis C virus (HCV) is a major ubiquitous pathogen responsible for acute and chronic hepatitis, cirrhosis and hepatocellular carcinoma. Its discovery was a major achievement, for which the Nobel prize has been awarded to three outstanding scientists. As a consequence of this major discovery, a number of extremely effective direct acting antivirals (DAAs) have been developed. These allow for complete viral cure in virtually all patients. This has transformed the HCV epidemic into a public health race to diagnose and link as many patients to care as possible. However, despite the existence of a complete cure, there remains still a residual risk of liver decompensation, as well as the emergence of primary liver cancer and extrahepatic tumors. Interestingly, chronic HCV infection is the only model of chronic infection that can now be easily cured. However, viral cures can leave behind epigenetic scars of antigen-specific immune dysfunction and exhaustion that often cannot be restored. Finally, the greatest challenge is now to develop an effective vaccine that, even though unable to induce sterilizing immunity, may nonetheless prevent chronic liver disease.

Prof. Dr. Mario Mondelli
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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Keywords

epigenetic signatures
public health
vaccines
hepatocellular carcinoma
extrahepatic cancer
liver decompensation
elimination
diagnosis
linkage to care

Published Papers (4 papers)

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Research

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13 pages, 1209 KiB

Open AccessArticle

Depression and Cognitive Dysfunction in Patients with Chronic Hepatitis C: Correlation with Viral Replication in the Peripheral Blood Mononuclear Cells and Cytokines in Serum

by Marek Radkowski, Tomasz Kryczka, Bogna Szymańska-Kotwica, Hanna Berak, Andrzej Horban, Tomasz Pawłowski, Karol Perlejewski and Tomasz Laskus

Int. J. Mol. Sci. 2023, 24(20), 15351; https://doi.org/10.3390/ijms242015351 - 19 Oct 2023

Cited by 1 | Viewed by 1094

Abstract

Chronic hepatitis C virus (HCV) infection is commonly associated with depression and cognitive dysfunction, the cause of which could be related to the HCV neuroinvasion and/or state of chronic inflammation. Viral sequences and proteins were previously detected in the brain and since blood leukocytes can cross the blood–brain barrier, they could provide viral access to the CNS. Eighty chronic hepatitis C patients were tested for viral replication in PBMCs (detection of the HCV RNA-negative strand) and serum cytokines. Depression was assessed by the Beck Depression Inventory (BDI), neuroticism by the Eysenck Personality Inventory (N/EPO-R), and anxiety by the State-Trait Anxiety Inventory (STAI) while neurocognitive testing included the Wisconsin Card Sorting Test (WCST), Ruff Figural Fluency Test (RFFT), California Verbal Learning Test (CVLT), and Grooved Pegboard Test (GPT). The HCV RNA-negative strand was detected in PBMCs from 24 (30%) patients and these patients had significantly higher BDI scores (median 12.5 [IQR] 6.3–20.5 vs. median 8.00 [IQR] 3–12; p = 0.013). Both depression and anxiety correlated positively with IL-8 while cognitive flexibility, executive function, problem-solving skills, memory, and motor functioning correlated negatively with some proinflammatory cytokines. Our findings suggest that due to chronic HCV infection, the brain function is negatively affected by both viral replication in PBMCs and by the immune activation state. Full article

(This article belongs to the Special Issue Hepatitis C Virus: Pathogenetic Mechanisms, Residual Problems after Cure and Hopes for Elimination)

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Review

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15 pages, 2090 KiB

Open AccessReview

Hepatitis C Virus and the Host: A Mutual Endurance Leaving Indelible Scars in the Host’s Immunity

by Mario U. Mondelli, Sabrina Ottolini, Barbara Oliviero, Stefania Mantovani, Antonella Cerino, Dalila Mele and Stefania Varchetta

Int. J. Mol. Sci. 2024, 25(1), 268; https://doi.org/10.3390/ijms25010268 - 23 Dec 2023

Cited by 1 | Viewed by 1314

Abstract

Hepatitis C virus (HCV) has spread worldwide, and it is responsible for potentially severe chronic liver disease and primary liver cancer. Chronic infection remains for life if not spontaneously eliminated and viral persistence profoundly impairs the efficiency of the host’s immunity. Attempts have been made to develop an effective vaccine, but efficacy trials have met with failure. The availability of highly efficacious direct-acting antivirals (DAA) has created hope for the progressive elimination of chronic HCV infections; however, this approach requires a monumental global effort. HCV elicits a prompt innate immune response in the host, characterized by a robust production of interferon-α (IFN-α), although interference in IFN-α signaling by HCV proteins may curb this effect. The late appearance of largely ineffective neutralizing antibodies and the progressive exhaustion of T cells, particularly CD8 T cells, result in the inability to eradicate the virus in most infected patients. Moreover, an HCV cure resulting from DAA treatment does not completely restore the normal immunologic homeostasis. Here, we discuss the main immunological features of immune responses to HCV and the epigenetic scars that chronic viral persistence leaves behind. Full article

(This article belongs to the Special Issue Hepatitis C Virus: Pathogenetic Mechanisms, Residual Problems after Cure and Hopes for Elimination)

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21 pages, 902 KiB

Open AccessReview

HCV and HCC Tango—Deciphering the Intricate Dance of Disease: A Review Article

by Ivana Milosevic, Nevena Todorovic, Ana Filipovic, Jelena Simic, Marko Markovic, Olja Stevanovic, Jovan Malinic, Natasa Katanic, Nikola Mitrovic and Natasa Nikolic

Int. J. Mol. Sci. 2023, 24(22), 16048; https://doi.org/10.3390/ijms242216048 - 7 Nov 2023

Viewed by 1461

Abstract

Hepatitis C virus (HCV) is a major cause of hepatocellular carcinoma (HCC) accounting for around one-third of all HCC cases. Prolonged inflammation in chronic hepatitis C (CHC), maintained through a variety of pro- and anti-inflammatory mediators, is one of the aspects of carcinogenesis, followed by mitochondrial dysfunction and oxidative stress. Immune response dysfunction including the innate and adaptive immunity also plays a role in the development, as well as in the recurrence of HCC after treatment. Some of the tumor suppressor genes inhibited by the HCV proteins are p53, p73, and retinoblastoma 1. Mutations in the telomerase reverse transcriptase promoter and the oncogene catenin beta 1 are two more important carcinogenic signaling pathways in HCC associated with HCV. Furthermore, in HCV-related HCC, numerous tumor suppressor and seven oncogenic genes are dysregulated by epigenetic changes. Epigenetic regulation of gene expression is considered as a lasting “epigenetic memory”, suggesting that HCV-induced changes persist and are associated with liver carcinogenesis even after cure. Epigenetic changes and immune response dysfunction are recognized targets for potential therapy of HCC. Full article

(This article belongs to the Special Issue Hepatitis C Virus: Pathogenetic Mechanisms, Residual Problems after Cure and Hopes for Elimination)

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Graphical abstract

11 pages, 579 KiB

Open AccessReview

Hepatocellular Carcinoma Prevention in the Era of Hepatitis C Elimination

by Jeffrey V. Lazarus, Camila A. Picchio and Massimo Colombo

Int. J. Mol. Sci. 2023, 24(18), 14404; https://doi.org/10.3390/ijms241814404 - 21 Sep 2023

Cited by 5 | Viewed by 1805

Abstract

The hepatitis C virus (HCV), a single-stranded RNA virus belonging to the Flaviviridae family, is a major cause of hepatocellular carcinoma (HCC) worldwide. Tumors caused by HCC have an increased mortality rate globally, which is more accentuated in Western countries. The carcinogenic potential of this virus is mediated through a wide range of mechanisms, spanning from the induction of chronic inflammation to oxidative stress and deregulation of cellular pathways by viral proteins. As the number of new infections continues unabated, HCC-related mortality should be prioritized through early detection, continued prevention of HCV transmission, and treatment of HCV with safe and efficacious direct antiviral agents (DAAs). People who inject drugs (PWID) are a significant reservoir of new HCV infections globally, and in order to eliminate hepatitis C as a global health threat, as set out by the World Health Organization, an integrated approach based on the optimization of care delivery and increased access to harm reduction and treatment for PWID is needed. Thanks to the development of safe and effective antiviral agents, eradication of the infection is now possible in almost all treated patients, leading to a significant reduction but not the elimination of the risk for HCC in cured patients. This is particularly relevant among aged populations who have cofactors of morbidity known to accelerate HCC progression, such as diabetes, obesity, and excessive alcohol consumption. Given the restless accumulation of individuals with cured HCV infection, the implementation of risk-stratified surveillance programs becomes impellent from a cost-effectiveness perspective, whereas the availability of a performant biomarker to predict HCC in cured patients remains an unmet clinical need. Full article

(This article belongs to the Special Issue Hepatitis C Virus: Pathogenetic Mechanisms, Residual Problems after Cure and Hopes for Elimination)

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