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Polymerases

Nevertheless, distinct epidemiological patterns are clearly distinguished in endemic regions compared to nonendemic areas

Nevertheless, distinct epidemiological patterns are clearly distinguished in endemic regions compared to nonendemic areas. Endemic countries were shown to have an overall HEV prevalence of 25% of all nona, non-B acute hepatitis cases,48 and while the anti-HEV immunoglobulin (Ig)G prevalence among healthy blood donors may be as high as 45% in some hyperendemic countries, reports JNJ-10229570 from industrialized countries, although highly variable from study to study, show prevalence ranging from 1% to 4%.49 Additional dramatic differences were observed in the size and frequency of outbreaks, overall attack rates, and duration of viremia.49 These issues are extensively reviewed by Kumar et al.9 Clinical features Historically, data on clinical manifestations of hepatitis E are available from basically two sources of evidence: 1) reports of HEV infection outbreaks and sporadic disease from highly endemic areas and 2) case reports and case series from developed nonendemic countries. for serosurveys and diagnosis of acute HEV infection is also needed. This review article summarizes the JNJ-10229570 current status of HEV infection end epidemiology with particular emphasis in transmission, diagnosis, and clinical management. in the family Hepeviridae.13,14 It is a small, nonenveloped, spherical particle of approximately 32C34 nm in diameter and has a single-stranded, positive sense ribonucleic acid (RNA) genome surrounded by an icosahedral capsid.1 HEV genome organization The HEV genome is 7,200 nucleotides (nt) in length, consisting of a short 5 untranslated region (27C35 nt), three discontinuous and partially overlapping open reading frames (ORFs) 1, 2, and 3, and a short 3 untranslated region (65C74 nt) that is terminated by a polyadenylated tract (Figure 1). The capped JNJ-10229570 5 end, essential for viral infectivity, and the 3 end of the viral genome are noncoding regions and cis-acting elements involved in the regulation of viral replication and translation.15,16 Open in a separate window Figure 1 Organization of the JNJ-10229570 hepatitis E virus genome. Notes: Scheme showing the organization of the three viral open reading frames (ORFs); ORF1 encodes a nonstructural polyprotein comprising a methyltransferase, Domain Y (nonfunction assigned), papain-like protease, proline-rich hypervariable region (HVR, in text), Domain X (nonfunction assigned), RNA helicase, and an RNA-dependent RNA polymerase; ORF2 encodes the capsid protein and ORF3 encodes a small phosphoprotein; nucleotide positions are relative to the genotype 1 Burmese SAR-55 isolate. Abbreviations: RNA, ribonucleic acid; nt, nucleotides. ORF1, the largest coding unit, encompassing approximately two thirds of the viral genome, is located at the 5 end and is approximately 5,000 nt in length. This region is involved in viral replication and protein processing, and it encodes nonstructural proteins including putative methyltransferase, guanylyl transferase, papain-like cysteine protease, RNA helicase, and RNA-dependent RNA polymerase.17,18 Also, some uncharacterized domains homologous to other animal and plant positive-strand RNA viruses have been identified in the ORF1.16 The hypervariable region, a noncoding region within ORF1 that displays substantial genetic diversity, was recently proposed to modulate the efficiency of HEV replication.19 Notably, the differences in the genome size among different HEV strains are confined mainly to this region.20 The viral ORF2 encodes the viral capsid protein of 660 amino acids that encapsidates the viral RNA genome.16 Capsid is the only structural protein and was shown to assemble into a highly structured multimer (60 copies).21,22 ORF3 overlaps the other two ORFs and encodes a small phosphoprotein of 123 amino acids that may cooperate in replication and cytoskeleton synthesis,23,24 and it is thought to interact with cellular mitogen-activated protein kinase phosphatase and other extracellular kinases, promoting cell survival through activation of intracellular signaling pathways.25 Genetic variability Although a single serotype has been proposed,26 extensive genomic diversity has been observed among HEV isolates.23 Human infecting HEV sequences have been classified into four major genotypes (1C4) according to analysis of the complete genome sequence and/or variable partial HEV genomic regions within the ORF1 and ORF2.27C29 However, the existence of a new HEV genotype infecting wild boar was recently been proposed.30 This, together with the increasing number of HEV and HEV-like sequences published in the last few years, which increase the number of potential new genotypes JNJ-10229570 or genetic groups, brought into question the current system of classification within the genus.31 According to the currently accepted system of classification, the four major HEV genotypes are further subclassified into subtypes, defined on the basis of five different phylogenetic reconstructions: 5 ORF1, 3 ORF1, 5 ORF2, 3 ORF2, and complete genome.28 HEV genotype 1 sequences are divided into five subtypes, 1aCe, and genotype 2 into two subtypes, 2a and 2b.28 Genotype 1 is responsible for most endemic and epidemic cases of HEV infection in Asia and has been also detected in small outbreaks from Cuba and sporadic cases from Venezuela and Uruguay, respectively1,32,33 (Figure 2). Genotype 2 is prevalent in Mexico (probably subtype 2a, based on the characterization of a single strain) and Africa (subtype 2b).1 By contrast, genotype 3 is widely distributed, and sequences of this genotype are extremely diverse,23 comprising ten (3aCj) subtypes. Genotype 4 sequences, even though they display high heterogeneity (subtypes 4aCg), are geographically restricted to Asia VEGFA and Central Europe (Figure 2).28,34 Recently, this subtype-based classification has also been challenged by Smith et al, in which an exhaustive molecular and phylogenetic analysis.