Hepatitis E virus (HEV) belonged to the family Hepeviridae and is a small quasi-enveloped or non-enveloped positive-sense single-stranded RNA virus, infecting mammals and birds (subfamily Orthohepevirinae) or fish (Parahepevirinae). The genus Paslahepevirus is responsible for hepatitis in humans [1]. HEV genome is characterized by three Open Reading Frames (ORFs): ORF1, ORF2 and ORF3 encoding nonstructural proteins, such as polymerase (RdRp), capsid protein and multifunctional phosphoprotein, respectively [1]. Sequences of whole or partial genome carried out by sequencing methodologies, followed by molecular analysis, is the way to classify HEV genetic variants. The virus is classified into eight genotypes (from HEV1 to HEV8). HEV1 and HEV2, are mainly transmitted by contaminated water in developed countries and infect only humans. Interestingly, very recently Liu and colleagues showed the efficient infection by HEV1 of Mongolian gerbil, which could be used as animal model to investigate viral immune pathogenesis and to evaluate vaccines or antiviral agents [2,3]. On the other hands, HEV3 and HEV4 infect both humans and animals, due to their genetic characteristics, and are responsible of locally acquired infection [[4], [5], [6]].

Genome variability significantly drive transmission route, pathogenesis, diseases severity and therapy response [4,7]. In particular, the ORF1 mutations on viral quasispecies could facilitate persistence of infection and treatment resistance, whilst ORF2 mutations could influence disease severity [7]. The high frequency of new variants could be related to broader spectrum of hosts and the worldwide geographical distribution of different HEV genotypes/subtypes [5]. In Italy, HEV3 is a human emerging foodborne pathogen, considering the increasing number of infected patients in the last ten years [8]. The consumption of undercooked or raw contaminated food, such as pig, deer or wild boar meat, is the main transmission route [9]. In Europe, between 2012 and 2014, the dynamic distribution of subtypes showed a decrease of HEV3f, HEV3g and HEV3e and a predominant prevalence of HEV3c, which was common detected in both animal and human population [10,11]. Several studies underlined the association between HEV‐IgG positivity and cirrhosis or chronic liver diseases [12]. Apparently, past HEV infection showed a more severe outcome in patients with non‐alcoholic fatty liver disease (NAFLD). On the contrary, the majority part of immunocompetent patients usually cleared infection spontaneously, developing antibodies, without antiviral treatment [12]. Ribavirin (RBV) in monotherapy or in combination should be considered in immunocompromised patients in cases of chronic or severe acute disease [13].

Herein we characterized by molecular analysis the autochthonous HEV strain detected during routine diagnosis from an immunocompetent patient with acute hepatitis infection. Phylogenetic analysis to identify the HEV correct genotype/subtype and to investigate possible transmission cluster was performed. Additionally, polymerase (ORF1) and capsid (ORF2) partial proteins to detect natural occurring mutations responsible of antiviral resistance or more pathogenicity were screened.