Hepatitis E: Molecular Virology and Pathogenesis

Abstract

Hepatitis E virus is a single, positive-sense, capped and poly A tailed RNA virus classified under the family Hepeviridae. Enteric transmission, acute self-limiting hepatitis, frequent epidemic and sporadic occurrence, high mortality in affected pregnants are hallmarks of hepatitis E infection. Lack of an efficient culture system and resulting reductionist approaches for the study of replication and pathogenesis of HEV made it to be a less understood agent. Early studies on animal models, sub-genomic expression of open reading frames (ORF) and infectious cDNA clones have helped in elucidating the genome organization, important stages in HEV replication and pathogenesis. The genome contains three ORF's and three untranslated regions (UTR). The 5 0 distal ORF, ORF1 is translated by host ribosomes in a cap dependent manner to form the non-structural polyprotein including the viral replicase. HEV replicates via a negative-sense RNA intermediate which helps in the formation of the positive-sense genomic RNA and a single bi-cistronic sub-genomic RNA. The 3 0 distal ORF's including the major structural protein pORF2 and the multifunctional host interacting protein pORF3 are translated from the sub-genomic RNA. Pathogenesis in HEV infections is not well articulated, and remains a concern due to the many aspects like host dependent and genotype specific variations. Animal HEV, zoonosis, chronicity in immunosuppressed patients, and rapid decompensation in affected chronic liver diseased patients warrants detailed investigation of the underlying pathogenesis. Recent advances about structure, entry, egress and functional characterization of ORF1 domains has furthered our understanding about HEV. This article is an effort to review our present understanding about molecular biology and pathogenesis of HEV. ( J CLIN EXP HEPATOL 2013;3:114-124) H epatitis E virus was first identified in 1983 as the agent responsible for the large scale waterborne epidemics of acute, self-limiting hepatitis in developing nations.1 It was shown to be a naked 28-34 nm virus-like particle with spikes and inundations. 1,2Successful use of non-human primate models for HEV propagation helped in its isolation, cloning and sequencing and as presumed turned out to be an RNA virus.3,4 It had a $7.2 kb single stranded genome with sequence homology to other positive-sense RNA viruses. 4,5 Computer based genome annotation revealed three overlapping open reading frames ORF1, ORF2 and ORF3.4,5 The longest ORF, ORF1 formed the 5 0 distal end of the genome and coded for the non-structural replication proteins including methyltransferase, protease, helicase, and RNA dependent RNA polymerase (RdRp). The 30 distal ORF, ORF2 coded for an arginine rich protein, together with immunodominant sero-reactivity and agglutination against the expressed epitopes, it was predicted to be the major structural protein. A third ORF, ORF3 coded for a small protein thought to be a minor structural protein. [4][5][6] Molecular characterization and replication model of HEV remained...

The RNA genome of hepatitis E virus robustly triggers an antiviral interferon response

“…Our findings that the host cells can rapidly recognize the incoming HEV genomic ssRNA and evolve potent antiviral responses may explain the asymptomatic infection in the general population. A subset of patients with acute hepatitis eventually clears the infection through active virus–host interactions, although pregnant women bear high risk of developing fulminant hepatitis, with a mortality rate reaching 25% . In immunocompromised patients, chronic infection has been widely reported, which is conceivably attributed to compromised innate and adaptive immunity .…”

“…HEV is a single‐stranded positive‐sense RNA virus within the family Hepeviridae. The genome contains short 5′ and 3′ noncoding regions, 5′‐m 7 G cap, 3′‐poly A tail, and three open reading frames (ORF1, ORF2, and ORF3) . In patients, particularly in cases of acute infection with severe hepatitis, active virus–host interactions are likely the cause of pathogenesis but also the process of combating the infection .…”

Hepatitis E and Acute-on-Chronic Liver Failure

“…1,2 It is primarily transmitted through the fecal-oral route, and is the most common cause of acute viral hepatitis (AVH) globally. It causes large scale epidemics of AVH across the low-and middle income countries in Asia and Africa, and also causes sporadic cases of AVH in the same geographical region.…”

Hepatitis E: Epidemiology and Natural History

“…17 HEV is classified in genus Hepevirus and family Hepeviridae. 18 It consists of a group of closely-related viruses that, besides humans, infect other mammals such as pigs, rabbits, rats, deer, and mongoose.…”