Hepatitis E virus (HEV) is the major cause of enterically transmitted non-A, non-B hepatitis in many developing countries and is also endemic in many industrialized countries. Due to the lack of an effective cell culture system and a practical animal model, the mechanisms of HEV pathogenesis and replication are poorly understood. Our recent identification of swine HEV from pigs affords us an opportunity to systematically study HEV replication and pathogenesis in a swine model. In an early study, we experimentally infected specificpathogen-free pigs with two strains of HEV: swine HEV and the US-2 strain of human HEV. Eighteen pigs (group 1) were inoculated intravenously with swine HEV, 19 pigs (group 2) were inoculated with the US-2 strain of human HEV, and 17 pigs (group 3) were used as uninoculated controls. The clinical and pathological findings have been previously reported. In this expanded study, we aim to identify the potential extrahepatic sites of HEV replication using the swine model. Two pigs from each group were necropsied at 3, 7, 14, 20, 27, and 55 days postinoculation (DPI). Thirteen different types of tissues and organs were collected from each necropsied animal. Reverse transcriptase PCR (RT-PCR) was used to detect the presence of positive-strand HEV RNA in each tissue collected during necropsy at different DPI. A negative-strand-specific RT-PCR was standardized and used to detect the replicative, negative strand of HEV RNA from tissues that tested positive for the positive-strand RNA. As expected, positive-strand HEV RNA was detected in almost every type of tissue at some time point during the viremic period between 3 and 27 DPI. Positive-strand HEV RNA was still detectable in some tissues in the absence of serum HEV RNA from both swine HEV-and human HEVinoculated pigs. However, replicative, negative-strand HEV RNA was detected primarily in the small intestines, lymph nodes, colons, and livers. Our results indicate that HEV replicates in tissues other than the liver. The data from this study may have important implications for HEV pathogenesis, xenotransplantation, and the development of an in vitro cell culture system for HEV.Hepatitis E virus (HEV), the causative agent of hepatitis E, has been recognized as a major cause of enterically transmitted non-A, non-B hepatitis in many developing countries (1,30,37,39). Transmission of the virus occurs primarily by the fecal-oral route through contaminated drinking water in areas with poor sanitation. The disease affects mainly young adults, with a reported mortality rate of up to 25% for pregnant women (10, 14, 37, 39). In the United States, sporadic cases of acute hepatitis E without known risk factors have been documented and anti-HEV antibodies have been detected in a significant proportion of healthy individuals (21,28,32,37,39,45). HEV is a positive, single-stranded RNA virus without an envelope. The genome, which is about 7.5 kb in size, contains three open reading frames (ORFs) and a short 5Ј and 3Ј nontranslated region (13,18,31,38). ORF 1 is...

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