Liver Abnormalities after Elimination of HCV Infection: Persistent Epigenetic and Immunological Perturbations Post-Cure

Polyak, Stephen J.; Baumert, Thomas F.

doi:10.3390/pathogens10010044

Cited by 13 publications

(11 citation statements)

References 88 publications

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“…Our data show an improvement in these immune and liver disease biomarkers in plasma (immune exhaustion (PD1), chemokines (CXCL10, CCL2, and CXCL8), and cytokines (IL10)) after achieving SVR with DAA therapy in HIV/HCV-coinfected individuals. These results are similar to those found in HCV-monoinfected persons, in whom immune and liver function improved after HCV clearance by DAA, although normalization of the immune system after SVR is not always achieved ( 54 , 55 ). Regarding HIV/HCV-coinfected patients, there are limited data on their status following DAA therapy.…”

Section: Discussionsupporting

confidence: 86%

HCV Cure With Direct-Acting Antivirals Improves Liver and Immunological Markers in HIV/HCV-Coinfected Patients

et al. 2021

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Hepatitis C virus (HCV) cure after all-oral direct-acting antiviral (DAA) therapy greatly improves the liver and immune system. We aimed to assess the impact of this HCV clearance on immune system-related markers in plasma and the gene expression profile in human immunodeficiency virus (HIV)/HCV-coinfected patients with advanced cirrhosis. We performed a prospective study on 33 HIV/HCV-coinfected patients at baseline and 36 weeks after the sustained virological response. Gene expression was evaluated by RNA-seq analysis on peripheral blood mononuclear cells (PBMCs) and plasma biomarkers by multiplex immunoassays. We found a decrease in plasma biomarkers (PD1, PDL1, CXCL10, CXCL8, IL12p70, IL10, and TGFβ) and liver disease markers (stiffness measurement (LSM), hepatic venous pressure gradient (HVPG), and transaminases, among others). Furthermore, decreased plasma levels of CXCL8, CXCL10, IL10, and PD1 were associated with reduced LSM values. We also found two upregulated (HAS1 and IRG1) and 15 downregulated (CXCL11, CCL8, CCL7, CCL2, ADARB2, RRAD, MX1, SIGLEC1, IFI44L, IFI44, IFI27, IFI6, IFIT3, IFIT1B, and IFIT1) genes at the end of follow-up, all interferon-stimulated genes (ISGs) grouped into four pathways (“cytokine-cytokine receptor interaction”, “viral protein interaction with cytokine and cytokine receptor”, “chemokine signaling pathway”, and “hepatitis C”). Additionally, the decrease in most of these ISGs was significantly related to reduced LSM and HVPG values. In conclusion, HIV/HCV-coinfected patients with advanced-HCV-related cirrhosis who eradicated HCV following DAA therapy exhibited an improvement in liver disease markers and a significant decrease in plasma biomarkers and gene expression related to antiviral/inflammatory response, particularly in levels of several chemokines and ISGs.

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Section: Discussionsupporting

confidence: 86%

HCV Cure With Direct-Acting Antivirals Improves Liver and Immunological Markers in HIV/HCV-Coinfected Patients

et al. 2021

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“…Our data suggest that ANGPTL-3 may be one of many genes belonging to the host transcriptome, secretome, epigenome and immunome that retain their expression levels after successful HCV eradication in patients with advanced liver damage. These genes are believed to be part of a residual HCV fingerprint that has been suggested to promote hepatocarcinogenesis in some cured patients [ 21 , 22 , 63 , 64 ]. Surprisingly, similar persistently expressed immunoregulatory signatures were even discovered in acutely infected HCV patients who received early DAA treatment [ 65 ].…”

Section: Discussionmentioning

confidence: 99%

“…Evidently, the HCV-mediated reprogramming of the host metabolism, epigenome and immunity and the constant deregulation of cellular signalling and hepatic gene expression lead to the establishment of a viral fingerprint that persistently remains after viral eradication. It is thought that these alterations may collectively promote HCC development and progression depending on the extent of the existing liver damage in some cured patients [ 9 , 10 , 21 , 22 , 23 ].…”

Section: Introductionmentioning

confidence: 99%

Differential Expression of the Host Lipid Regulators ANGPTL-3 and ANGPTL-4 in HCV Infection and Treatment

Valiakou

Eliadis

Karamichali

et al. 2021

IJMS

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Host lipid metabolism reprogramming is essential for hepatitis C virus (HCV) infection and progression to severe liver disease. Direct-acting antivirals (DAAs) achieve a sustained virological response (SVR) in most patients, but virus eradication does not always protect against hepatocellular carcinoma (HCC). Angiopoietin-like protein-3 (ANGPTL-3) and angiopoietin-like protein-4 (ANGPTL-4) regulate the clearance of plasma lipids by inhibiting cellular lipase activity and possess emerging roles in tumourigenesis. We used ELISA and RT-qPCR to investigate ANGPTL-3 and ANGPTL-4 expression in HCV patients with characterised fibrosis throughout the natural history of hepatitis C and in long-term HCV infection in vitro, before and after DAA treatment. ANGPTL-3 was decreased in patients with advanced fibrosis compared to other disease stages, while ANGPTL-4 was progressively increased from acute infection to cirrhosis and HCC, peaking at the advanced fibrosis stage. Only ANGPTL-3 mRNA was down-regulated during early infection in vitro, although both ANGPTLs were increased later. DAA treatment did not alter ANGPTL-3 levels in advanced fibrosis/cirrhosis and in HCV infection in vitro, in contrast to ANGPTL-4. The association between ANGPTLs and fibrosis in HCV infection was underlined by an inverse correlation between the levels of ANGPTLs and serum transforming growth factor- β (TGF-β). Collectively, we demonstrate the pivotal role of advanced fibrosis in defining the expression fate of ANGPTLs in HCV infection and after treatment and propose a role for ANGPTL-3 as a contributor to post-treatment deregulation of lipid metabolism that could predispose certain individuals to HCC development.

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“…Recently, Hamdane et al showed that epigenetic changes in H3K27ac levels are induced through direct interaction between HCV and hepatocytes and indirectly through liver fibrosis [59]. Importantly, several studies show that these changes persist after sustained viral response (SVR) to either DAAs or interferon-based therapies [60][61][62].…”

Section: Hepatitis C Virus (Hcv)mentioning

confidence: 99%

Viral Manipulation of the Host Epigenome as a Driver of Virus-Induced Oncogenesis

2021

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Tumorigenesis due to viral infection accounts for a high fraction of the total global cancer burden (15–20%) of all human cancers. A comprehensive understanding of the mechanisms by which viral infection leads to tumor development is extremely important. One of the main mechanisms by which viruses induce host cell proliferation programs is through controlling the host’s epigenetic machinery. In this review, we dissect the epigenetic pathways through which oncogenic viruses can integrate their genome into host cell chromosomes and lead to tumor progression. In addition, we highlight the potential use of drugs based on histone modifiers in reducing the global impact of cancer development due to viral infection.

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Liver Abnormalities after Elimination of HCV Infection: Persistent Epigenetic and Immunological Perturbations Post-Cure

Cited by 13 publications

References 88 publications

HCV Cure With Direct-Acting Antivirals Improves Liver and Immunological Markers in HIV/HCV-Coinfected Patients

HCV Cure With Direct-Acting Antivirals Improves Liver and Immunological Markers in HIV/HCV-Coinfected Patients

Differential Expression of the Host Lipid Regulators ANGPTL-3 and ANGPTL-4 in HCV Infection and Treatment

Viral Manipulation of the Host Epigenome as a Driver of Virus-Induced Oncogenesis

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