The hepatitis E virus ORF3 protein regulates the expression of liver-specific genes by modulating localization of hepatocyte nuclear factor 4.

The hepatitis E virus (HEV) is a small RNA virus and the cause of acute viral hepatitis E. The open reading frame 3 protein (pORF3) of HEV appears to be a pleiotropic regulatory protein that helps in the establishment, propagation and progression of viral infection. However, the global cellular effects of this protein remain to be explored. In the absence of traditional in vitro viral infection systems or efficient replicon systems, we made an adenovirus based ORF3 protein expression system to study its effects on host cell gene expression. We infected Huh7 hepatoma cells with recombinant adenoviruses expressing pORF3 and performed microarray-based gene expression analyses. Several genes down regulated in pORF3-expressing cells were found to be under regulation of the liver-enriched hepatocyte nuclear factor 4 (HNF4), which regulates hepatocyte-specific gene expression. While HNF4 localizes to the nucleus, its phosphorylation results in impaired nuclear localization of HNF4. Here we report that pORF3 increases HNF4 phosphorylation through the ERK and Akt kinases, which results in impaired nuclear translocation of HNF4 and subsequently the down modulation of HNF4-responsive genes in pORF3-expressing cells. We propose that modulation of several hepatocyte specific genes by pORF3 will create an environment favorable for viral replication and pathogenesis.

Global distribution of novel rhinovirus genotype.

Global surveillance for a novel rhinovirus genotype indicated its association with community outbreaks and pediatric respiratory disease in Africa, Asia, Australia, Europe, and North America. Molecular dating indicates that these viruses have been circulating for at least 250 years.

Molecular epidemiology of rotaviruses in India.

Rotaviruses cause an estimated 140 million cases of gastroenteritis and 800,000 deaths in children between the ages of 6 months to 2 yr in developing countries. In India, one of every 250 children or about 100-150,000 children die of rotavirus diarrhoea each year. The prevalence of rotavirus diarrhoea in India has been found to vary from 5-71 per cent in hospitalized children <5 yr of age with acute gastroenteritis. The seasonal variation of rotavirus diarrhoea in India varies in different geographical regions with high incidence in winter months at low relative humidity in north India. The distinctive features of rotavirus infection in India include the occurrence of severe disease at an early age and common neonatal rotavirus infections which are often asymptomatic. Rotavirus shows genetic and antigenic diversity in terms of subgroup, electropherotypes and G and P serotypes/genotypes. There are a few studies in terms of prevalence of different antigenic and genetic variants from various regions of India. In most studies on subgroup distribution from India a higher prevalence of subgroup II was reported compared to subgroup I. Electropherotyping has also demonstrated that a number of multiple electropherotypes co-circulate at one time in a particular community leading to extensive genomic variation and the appearance of new strains which may become the predominant electropherotype during the peak season. The most common G types reported from India are G1 and G2 and P types are P[4] and P[8]. A significant number of children also have mixed rotavirus infections. G9 strains are also quite commonly seen in Indian children. In addition P6 strains of probable bovine origin have been reported from India. A novel neonatal strain P type 11 human rotavirus (116 E) was isolated from neonates in Delhi, the VP4 of which was closely related to the bovine serotype G10P[11] strain B223 and VP7 was closely related to the human serotype G9 strain. Another neonatal strain G10P[11] was reported from Bangalore. G10P[11] strains also have a high prevalence in calves with diarrhoea, in India. The occurrence of these unusual rotavirus strains which are natural reassortants of human and bovine rotaviruses, suggests that reassortment may be an important mechanism for generation of rotavirus strains of newborns. This is catalyzed by the age old traditions of calves and humans living in the same household and socio-economic conditions in India. The diversity of rotavirus strains and the high prevalence of mixed infections in India are unique features of rotavirus epidemiology in India and emphasizes that vaccines should be formulated against a broad range of strains. Another important aspect is that vaccines in India should also target G9 strains. Since neonates acquiring rotavirus infection are protected against severe diarrhoea, neonatal rotavirus strains can be effective potential vaccine candidates and vaccines based on these neonatal strains are being indigenously developed in India.