Department and institution: Department of Genomics and Molecular Biology INGM - Istituto Nazionale Genetica Molecolare
Keywords: HCV; Chronic Viral Hepatitis; Liver Cancer; Interferon; Long Noncoding RNA.
It is estimated that 3% of the world’s population are chronically infected by the hepatitis C virus (HCV). Most infections become chronic and over time evolve into chronic hepatitis. The most unwanted complication of chronic hepatitis is cirrhosis, a massive liver fibrosis, which can lead to liver failure and hepatocellular carcinoma.
The pathological outcome of HCV infection depends on viral- as well as host determinants. The development of in vitro cell culture systems has lead to significant progress in the understanding of the HCV life cycle, in particular viral replication, while viral entry and viral exit are still enigmatic. Upon infection, HCV subverts many different cellular pathways in favor of its own life cycle and virus-host interactions play a crucial role for the establishment of chronic infection. One metabolic pathway drastically altered upon HCV infection is the phosphatidylinositol-4 phosphate (PI4P) pathway. HCV induces a specialized membranous compartment, called membranous web, which is highly enriched with phosphatidylinositol-4 phosphate (PI4P). Phosphatidylinositol 4-Kinase IIIα (PI4KIIIα), the cellular kinase crucially involved in the synthesis of the HCV membranous web, is recruited by the HCV nonstructural protein 5A (NS5A) and it is believed that this interaction stimulates PI4KIIIα kinase activity. Our laboratory is interested in understanding the molecular mechanisms of how HCV influences the PI4P pathway and how this subversion of PI4P metabolism influences the pathogenesis of chronic liver disease and progression to liver cancer.
Another focus of our laboratory is the identification of viral and host genetic determinants that influence liver disease progression and response to antiviral therapy. Whole-genome association studies identified host single nucleotide polymorphisms (SNPs) near the genomic region encoding IL28B as strongly associated with viral clearance in HCV genotype 1 subjects and we confirmed the role of IL28B genotype also in HCV genotype 4 patients in collaboration with the A.M. Migliavacca Center for Liver Disease (Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico).
Recently, HCV variants characterized by genomic deletions have been highlighted in the serum and liver of chronic HCV patients. These defective genomes contain large in-frame deletions affecting prevalently the Envelope proteins, and are efficiently packaged into infectious viral particles when co-expressed together with full-length viral genome. HCV carrying defective genomes will transduce self-replicating HCV subgenomes, resulting in the persistent expression of HCV proteins even in the absence of co-infection with the wild-type helper virus. To evaluate the hypothesis that HCV defective particles are cytopathogenic variants that could affect the severity of liver disease, we are employing a two-fold approach: (I) in-vitro dissection of the cythopathogenic effect of HCV defective variants and (II) ex-vivo evaluation of the association of HCV defective genomes with clinical features in chronic hepatitis C patients.
Ongoing Projects include:
- Role of phosphoinositol 4-phosphate metabolism and PI4K kinases in the pathogenesis of chronic liver disease and liver cancer.
- Identification of host and viral genetic determinants implicated in the progression of hepatic and extra-hepatic diseases associated with chronic hepatitis C (i.e. liver fibrosis, cirrhosis, hepatocarcinoma).
- Characterization of long non-coding RNAs induced by viral infection and/or interferon treatment in hepatic cells.
Raffaele De Francesco is internationally recognized for his pioneering work on many different aspects of the molecular virology of the hepatitis C virus (HCV) and for his research activity in the field of anti-HCV drug discovery and drug resistance. He is the author or co-author of over 100 highly cited research articles published in international peer-reviewed journals (H-index=54). Raffaele De Francesco received his degree in biology from the University of Milan. Subsequently, he was a postdoctoral fellow at Emory University, Atlanta, U.S.A., and at the European Molecular Biology Laboratory, Heidelberg, Germany.
Between 1991 and 2008, Raffaele De Francesco worked at IRBM/Merck Research Laboratory in Rome (Italy), where he focused on the identification of molecular targets for antiviral therapy and on the development HCV small-molecule inhibitors as novel agents for the treatment chronic hepatitis C. From October 2008, he is the Virology Program Leader at the Istituto Nazionale Genetica Molecolare “Romeo ed Enrica Invernizzi” (INGM, Milano, Italy), a newly founded non-profit translational research organization aimed at the discovery of novel therapeutic and diagnostic approaches in the field of infectious diseases and cancers associated with chronic infections.
1. Hepatitis C virus-specific directly acting antiviral drugs Delang L, Neyts J, Vliegen I, Abrignani S, Neddermann P, De Francesco R. Current Topics in Microbiology and Immunology. 369: 289-320, 2013.
2. New horizons in Hepatitis C antiviral therapy with direct-acting antivirals Aghemo A, De Francesco R. Hepatology. 2013; 10.1002/hep.26371
3. IL28B polymorphisms predict interferon-related hepatitis B surface antigen seroclearance in genotype D hepatitis B e antigen-negative patients with chronic hepatitis B Lampertico P, Viganò M, Cheroni C, Facchetti F, Invernizzi F, Valveri V, Soffredini R, Abrignani S, De Francesco R, Colombo M. Hepatology. 2012; 57 (3) , pp. 890-896
4. Metabolism of Phosphatidylinositol 4-Kinase IIIα-Dependent PI4P Is Subverted by HCV and Is Targeted by a 4-Anilino Quinazoline with Antiviral Activity. Bianco A, Reghellin V, Donnici L, Fenu S, Alvarez R, Baruffa C, Peri F, Pagani M, Abrignani S, Neddermann P, De Francesco R. PLoS Pathog. 2012 Mar;8(3):e1002576. Epub 2012 Mar 8.
5. Genetic variation in the interleukin-28B gene is not associated with fibrosis progression in patients with chronic hepatitis C and known date of infection. Marabita F, Aghemo A, De Nicola S, Rumi MG, Cheroni C, Scavelli R, Crimi M, Soffredini R, Abrignani S, De Francesco R, Colombo M. Hepatology. 2011 Oct;54(4):1127-34. doi: 10.1002/hep.24503. Epub 2011 Aug 19.
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