2/19/2023 0 Comments Mate translate virusFurther investigations revealed that ORF4 is expressed only in genotype-1 and it acts by interacting with multiple viral and host proteins and cooperates with host eEF1α1 (eukaryotic elongation factor 1 isoform 1) to control the activity of viral RNA dependent RNA polymerase. Here, we report that endoplasmic reticulum stress inducing agents promote genotype-1 HEV replication by initiating cap-independent, internal translation mediated synthesis of a novel viral factor, which we have named ORF4. With the goal of developing an efficient laboratory model of genotype-1 HEV, we attempted to identify a permissive cellular condition that would allow efficient viral replication in human hepatoma cells. However, genotype-1 virus, which is known to infect human and is a major public health concern in south Asian countries, replicates poorly in mammalian cell culture and no other efficient model exists to investigate the viral life cycle. Genotype-3 and 4 viruses have been successfully propagated in the laboratory in mammalian cell culture. Genotype-3 and 4 viruses infect humans and a few animals (such as pigs, deer, mongeese) and have been reported from industrialized countries. Even after 30 years of discovery of the virus, little information exists regarding viral life cycle and replication machinery. Another peculiar characteristic of HEV is attributed to its ability to cause high mortality (~30%) in infected pregnant women. Recent reports also indicate HEV induced acute and chronic hepatitis in organ transplant patients. Owing to lack of sanitation and unavailibility of safe drinking water, populations of developing and resource starved countries are prone towards HEV infection. It is a small positive strand RNA virus, which is transmitted through the feco-oral route. Hepatitis E virus (HEV) is one of the most common causes of acute and sporadic viral hepatitis. These findings reveal a positive role of ER stress in promoting genotype-1 HEV replication and pave the way towards development of an efficient model of the virus. Furthermore, human hepatoma cells that stably express ORF4 or engineered proteasome resistant ORF4 mutant genome permitted enhanced viral replication. In association with eEF1α1, ORF4 stimulated viral RdRp activity. ORF4 interacted with multiple viral and host proteins and assembled a protein complex consisting of viral helicase, RNA dependent RNA polymerase (RdRp), X, host eEF1α1 (eukaryotic elongation factor 1 isoform-1) and tubulinβ. ORF4 protein sequence is mostly conserved among genotype-1 HEV isolates and ORF4 specific antibodies were detected in genotype-1 HEV patient serum. Importantly, ORF4 expression and stimulatory effect of ER stress inducers on viral replication is specific to genotype-1. Here, we report that endoplasmic reticulum (ER) stress promotes genotype-1 HEV replication by inducing cap-independent, internal initiation mediated translation of a novel viral protein (named ORF4). However, genotype-1 virus replicates poorly in mammalian cell culture and no other efficient model exists to study its life cycle. ![]() ![]() Genotype-5, 6 and 7 viruses are known to infect animals such as wild boar and camel, respectively. Sporadic cases of genotype-3 and 4 infection in human and animals such as pigs, deer, mongeese have been reported primarily from industrialized countries. Of the seven viral genotypes, genotype-1 virus infects humans and is a major public health concern in South Asian countries. ![]() It has also been reported to cause acute and chronic hepatitis in organ transplant patients. Though self-limiting in normal individuals, it results in ~30% mortality in infected pregnant women. Hepatitis E virus (HEV) causes acute hepatitis in many parts of the world including Asia, Africa and Latin America.
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