Advances in Hepatitis E Virus Biology and Pathogenesis

Abstract

Hepatitis E virus (HEV) is one of the causative agents for liver inflammation across the world. HEV is a positive-sense single-stranded RNA virus. Human HEV strains mainly belong to four major genotypes in the genus Orthohepevirus A, family Hepeviridae. Among the four genotypes, genotype 1 and 2 are obligate human pathogens, and genotype 3 and 4 cause zoonotic infections. HEV infection with genotype 1 and 2 mainly presents as acute and self-limiting hepatitis in young adults. However, HEV infection of pregnant women with genotype 1 strains can be exacerbated to fulminant hepatitis, resulting in a high rate of case fatality. As pregnant women maintain the balance of maternal-fetal tolerance and effective immunity against invading pathogens, HEV infection with genotype 1 might dysregulate the balance and cause the adverse outcome. Furthermore, HEV infection with genotype 3 can be chronic in immunocompromised patients, with rapid progression, which has been a challenge since it was reported years ago. The virus has a complex interaction with the host cells in downregulating antiviral factors and recruiting elements to generate a conducive environment of replication. The virus-cell interactions at an early stage might determine the consequence of the infection. In this review, advances in HEV virology, viral life cycle, viral interference with the immune response, and the pathogenesis in pregnant women are discussed, and perspectives on these aspects are presented.

Hepatitis E and Pregnancy: An Unholy Alliance Unmasked from Kashmir, India

“…Thus, higher mortality of epidemic hepatitis E in pregnancy is genotype-specific and associated with HEV-gt1 and not with other genotypes causing human infections, namely HEV-gt2, HEV-gt3, and HEV-gt4. However, adverse pregnancy outcomes including miscarriage and stillbirths have been reported in pregnant rabbits experimentally infected with HEV-gt3 and HEV-gt4 [ 122 , 123 , 124 ].…”

“…Among the HEV family, HEV-gt1 alone has ORF4 which encodes a protein, pORF4 of 124 aa [ 38 , 39 ]. The encoded pORF4 by the HEV-gt1 genome interact with other viral and host proteins, enhance viral polymerase activity and promote viral replication [ 123 ]. HEV-gt1, and not HEV-gt3, causes necrosis and apoptosis in the maternal–fetal interface possibly caused by mitochondrial damage and activation of caspase family membranes [ 151 ].…”

“…HEV-gt1 infection in pregnant women causes several alterations in innate and adaptive immune response, which helps virus replication and increases the severity of disease in the pregnant women [ 123 ]. Pregnant women with HEV-ALF have impaired macrophage phagocytic activity and downregulation of TLR3 and TLR9 expression, impeding MyD88-mediated IFN production [ 158 ].…”

Human pathogenic RNA viruses establish non-competing lineages by occupying independent niches

“…In the case of zoonotic viruses, distinct lineages can originate when the same virus species is introduced from different animal reservoirs, which could support ongoing diversification and lineage turnover not observed in the human population. This is how some Orthohepevirus A (OHVA) GLs (37) and possibly some TBEV and WNV GLs (33,38) could originate. However, even in this case, the maintenance of multiple niches with low turnover within human populations requires spatiotemporal or immunological separation.…”

“…S17). Both these genes are likely to be involved in host adaptation following zoonosis (37,48). Further, a two to five fold increase in mean dN/dS was detected for DENV, WNV and HCV GLs across most genes relative to the complete phylogeny (Fig.…”