A tightly clustered hepatitis E virus genotype 1a is associated with endemic and outbreak infections in Bangladesh

Abstract

Background Hepatitis E virus (HEV) infection is endemic in Bangladesh and there are occasional outbreaks. The molecular characteristics and pathogenesis of endemic and outbreak HEV strains are poorly understood. We compared the genetic relatedness and virulence associated mutations of endemic HEV strains with outbreak strains. Methods We analyzed systematically collected serum samples from HEV immunoglobulin M (IgM) positive patients attended at Bangabandhu Sheikh Mujib Medical University, Dhaka from August 2013 to June 2015. HEV RNA positive samples were subjected to whole genome sequencing. Genotype and subtype of the strains were determined by phylogenetic analysis. Virulence associated mutations e.g. acute viral hepatitis (AVH), fulminant hepatic failure (FHF), chronic hepatitis, ribavirin treatment failure (RTF), B and T cell neutralization epitopes were determined. Results 92 HEV immunoglobulin M (IgM) antibody positive plasma samples (43 in 2013–2014 and 49 in 2014–2015) were studied. 77.1% (70/92) of the samples were HEV RNA positive. A 279 bp open reading frame (ORF) 2 and ORF 3 sequence was obtained from 54.2% (38/70) of the strains. Of these 38 strains, whole genome sequence (WGS) was obtained from 21 strains. In phylogenetic analysis of 38 (279 bp) sequence all HEV sequences belonged to genotype 1 and subtype 1a. Further phylogenetic analysis of 21 HEV WGS, Bangladeshi HEV sequences clustered with genotype 1a sequences from neighboring countries. Within genotype 1a cluster, Bangladesh HEV strains formed a separate cluster with the 2010 HEV outbreak strains from northern Bangladesh. 80.9 to 100% of the strains had A317T, T735I, L1120I, L1110F, P259S, V1479I, G1634K mutations associates AVH, FHF and RTF. Mutations in T cell recognition epitope T3, T5, T7 was observed in 76.1%, 100% and 100% of the strains respectively. Conclusion Strains of HEV genotype 1a are dominant in Bangladesh and are associated with endemic and outbreak of HEV infection. HEV isolates in Bangladesh have high prevalence of virulence associated mutations and mutation which alters antigenicity to B and T cell epitopes.

Two mutations in the ORF1 of genotype 1 hepatitis E virus enhance virus replication and may associate with fulminant hepatic failure

“…Our in vitro results regarding the potential role of these two mutations in viral pathogenicity and FHF are further corroborated by a recent study in which 21 HEV-1 whole-genome sequences were obtained from HEV IgM-positive patients from 2013 to 2015 in Bangladesh. These tightly clustered HEV strains were associated with HEV outbreaks and FHF/ALF ( 33 ). Remarkably, we found that the two unique amino acid mutations (A317T and V1120I) simultaneously occurred in 100% of all 21 HEV-1 genomes derived from FHF patients during HEV outbreaks from 2013 to 2015 in Bangladesh ( Fig.…”

“…2 and 3 ). Importantly, these same two unique mutations simultaneously occurred in 100% of 21 tightly clustered HEV-1 strains detected in outbreaks from Bangladesh, which are associated with FHF in patients ( 33 ). Furthermore, we demonstrated that a combinational mutant containing A317T/I1120I double mutations significantly increased HEV replication efficiency than either mutation alone ( Fig.…”

Hepatitis E Virus (HEV) Synopsis: General Aspects and Focus on Bangladesh

“…The study that revealed 29 small HEV outbreaks (≥ 2 laboratory-confirmed cases) identified from a single private laboratory suggests that the actual burden of HEV infection in Bangladesh is much more significant than previously described by WHO using data from large outbreaks alone [ 19 ]. Strains of HEV-1a are dominant in Bangladesh and are associated with endemic outbreaks of HEV infection [ 59 ], while the 2018 Chattogram outbreak was caused by HEV-1f [ 60 ]. When compared with HEV-1a strains from India, Nepal, Pakistan, and Myanmar; within genotype 1a cluster, Bangladesh HEV strains formed a separate cluster with the 2010 HEV outbreak strains from northern Bangladesh; about 100% of the strains had A317T, T735I, L1120I, L1110F, P259S, V1479I, G1634K mutations associates AVH, FHF and RTF [ 59 ].…”

“…Strains of HEV-1a are dominant in Bangladesh and are associated with endemic outbreaks of HEV infection [ 59 ], while the 2018 Chattogram outbreak was caused by HEV-1f [ 60 ]. When compared with HEV-1a strains from India, Nepal, Pakistan, and Myanmar; within genotype 1a cluster, Bangladesh HEV strains formed a separate cluster with the 2010 HEV outbreak strains from northern Bangladesh; about 100% of the strains had A317T, T735I, L1120I, L1110F, P259S, V1479I, G1634K mutations associates AVH, FHF and RTF [ 59 ].…”

Stability and Feasibility of Dried Blood Spots for Hepatitis E Virus Serology in a Rural Setting

“…Hepatitis E virus (HEV) is a major cause of acute hepatitis around the world, but with a disproportionately high burden in low-income countries, where pregnant women and their offspring are at particular risk of severe disease and death due to HEV genotype 1 in particular [1]. This genotype is common in many low-income countries such as Bangladesh [2], while genotypes 3 and 4 dominate in high-and middle-income countries [1]. Several public health interventions, including a new vaccine [3], could probably alleviate some of the burden.…”