Modelling of Hepatitis E virus RNA-dependent RNA polymerase genotype 3 from a chronic patient and in silico interaction analysis by molecular docking with Ribavirin.

Hepatitis E Virus (HEV) infection is an emergent zoonotic disease, where chronic hepatitis E associated to solid organ transplant (SOT) recipients, related to genotype 3, is the clinical manifestation of major concern. In this setting, ribavirin (RBV) treatment is the only available therapy, though drug-resistant variants could emerge leading to a therapeutic failure. Crystallographic structures have not been reported for most of the HEV proteins, including the RNA-polymerase (RdRp). Therefore, the mechanism of action of RBV against HEV and the molecular interactions between this drug and RdRp are largely unknown. In this work, we aimed to model in silico the 3 D structure of a novel HEV3 RdRp (HEV_C1_Uy) from a chronically HEV infected-SOT recipient treated with RBV and to perform a molecular docking simulation between RBV triphosphate (RBVT), 7-methyl-guanosine-5'-triphosphate and the modelled protein. The models were generated using I-TASSER server and validated with multiple bioinformatics tools. The docking analysis were carried out with AutoDock Vina and LeDock software. We obtained a suitable model for HEV_C1_Uy (C-Score=-1.33, RMSD = 10.4 ± 4.6 Å). RBVT displayed a binding affinity of -7.6 ± 0.2 Kcal/mol by molecular docking, mediated by 6 hydrogen-bonds (Q195-O14, S198-O11, E257-O13, S260-O2, O3, S311-O11) between the finger's-palm-domains and a free binding energy of 31.26 ± 16.81 kcal/mol by molecular dynamics simulations. We identified the possible HEV RdRp interacting region for incoming nucleotides or analogs and provide novel insights that will contribute to better understand the molecular interactions of RBV and the enzyme and the mechanism of action of this antiviral drug.Communicated by Ramaswamy H. Sarma.

Ribavirin treatment of a patient with chronic hepatitis E. First case reported in Latin America.

We describe a clinical case of a kidney transplant patient who presented a sudden elevation of his liver function tests. Once we ruled out the most frequent causes of acute hepatitis, serum tests for Hepatitis E were performed. Hepatitis E virus RNA was detected in blood and stools. After six months the virus was still detected. Ribavirin treatment was initiated with normalization of the serum aminotransferases and sustained virology response was achieved.

Hepatitis E virus: new faces of an old infection.

Hepatitis E virus is one of the most common causes of acute hepatitis worldwide, with the majority of cases occurring in Asia. In recent years, however, an increasing number of acute and chronic hepatitis E virus infections have been reported in industrialized countries. The importance of this infection resides in the associated morbidity and mortality. In acute cases, a high mortality rate has been reported in patients with previously undiagnosed alcoholic liver disease. Hepatitis E infection can become chronic in immunocompromised patients, such as solid organ transplant recipients, patients receiving chemotherapy, and HIV-infected patients, and lead to the development of hepatic fibrosis and cirrhosis. Hence, treatment strategies involving reductions in immunosuppressive regimens and therapy with ribavirin or peg-interferon have been evaluated. In terms of prevention, a promising new vaccine was recently licensed in China, although its efficacy is uncertain and potential adverse effects in risk groups such as chronic liver disease patients and pregnant women require investigation. In conclusion, physicians should be aware of hepatitis E as a cause of both acute and chronic hepatitis in immunocompromised patients. The best treatment option for HEV infection remains to be defined, but both ribavirin and peg-interferon may have a role in therapy for this condition.

Cirrhosis due to chronic hepatitis E infection in a child post-bone marrow transplant.

Chronic hepatitis E virus (HEV) infection occurs in immunosuppressed adults. We detected HEV ribonucleic acid in serum of an adolescent patient who had undergone bone marrow transplantation and subsequently presented with persistently increased aminotransferases and histologic chronic hepatitis, and eventually developed cirrhosis. Phylogenetic analysis revealed these HEV strains were similar to swine genotype 3a, suggesting a possible zoonosis.