Proline-Rich Hypervariable Region of Hepatitis E Virus: Arranging the Disorder.

Milagros Muñoz-Chimeno,Ana Avellon,David Rodriguez-Lazaro,Marta Hernandez,Alejandro Cenalmor,Maira Alejandra Garcia-Lugo

doi:10.3390/microorganisms8091417

Abstract

The hepatitis E virus (HEV) hypervariable region (HVR) presents the highest divergence of the entire HEV genome. It is characteristically rich in proline, and so is also known as the “polyproline region” (PPR). HEV genotype 3 (HEV-3) exhibits different PPR lengths due to insertions, PPR and/or RNA-dependent RNA polymerase (RdRp) duplications and deletions. A total of 723 PPR-HEV sequences were analyzed, of which 137 HEV-3 sequences were obtained from clinical specimens (from acute and chronic infection) by Sanger sequencing. Eight swine stool/liver samples were also analyzed. N- and C-terminal fragments were confirmed as being conserved, but they harbored differences between genotypes and were not proline-plentiful regions. The genuine PPR is the intermediate region between them. HEV-3 PPR contains a higher percentage (30.4%) of prolines than other genotypes. We describe for the first time: (1) the specific placement of HEV-3 PPR rearrangements in sites 1 to 14 of the PPR, noting that duplications are more frequently attached to sites 11 and 12 (AAs 74–79 and 113–118, respectively); (2) the cadence of repetitions follows a circular-like pattern of blocks A to J, with F, G, H, and I being the most frequent; (3) a previously unreported insertion homologous to apolipoprotein C1; and (4) the increase in frequency of potential N-glycosylation sites and differences in AAs composition related to duplications.

Highlights

Hepatitis E virus (HEV) infection is an important component of enteric-transmitted liver diseases and has a significant impact on public health
In addition to that described in HEV genotype 3 infection (HEV-3), we identified a single amino acid (AA) insertion between positions 122 and 123 in HEV-4 that was present in sequences from HEV-4c, HEV-4a, and HEV-4d
The main zoonotic genotypes, HEV-3 and HEV-4, showed substantive differences in length due to insertions and deletions. This phenomenon has been previously reported [20,24,26,27], we describe for the first time the specific location of HEV-3 polyproline region” (PPR) rearrangements, noting that PPR duplications were more attached to specific locations (AAs 74–79 and 113–118)

Summary

Introduction

Hepatitis E virus (HEV) infection is an important component of enteric-transmitted liver diseases and has a significant impact on public health. HEV genotype 3 infection (HEV-3) is a viral zoonosis transmitted to humans through consumption of meat from infected animals, mainly pig [2,3,4], wild boar [5,6,7], and deer [8]. HEV-3 is spreading worldwide and is the cause of acute mainly self-limited hepatitis. In immunocompetent and immunocompromised patients, hepatitis can be fulminant, while chronic infection has been only described in immunocompromised. ORF2 encodes the viral capsid protein and contains neutralizing epitopes of virus particles and is the target of humoral immune response [10,11]. Seven putative domains have been identified in ORF1: methyltransferase (MTase), Y domain, putative papain-like cysteine protease (PCP), the proline-rich hinge domain (PPR) or hypervariable region (HVR), the X domain, putative RNA helicase, and RNA-dependent RNA polymerase (RdRp) [14]

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