Rotavirus infection in children at risk of developing type 1 diabetes has been temporally associated with development of pancreatic islet autoantibodies. In this study, nonobese diabetic mice were shown to be susceptible to rhesus rotavirus infection and pancreatic islets from nonobese diabetic mice, nonobese diabetesresistant mice, fetal pigs, and macaque monkeys supported various degrees of rotavirus growth. Human rotaviruses replicated in monkey islets only. This islet susceptibility shows that rotavirus infection of the pancreas in vivo might be possible.Rotaviruses are the major cause of human infantile gastroenteritis worldwide, with multiple serotypes causing regular winter outbreaks until herd immunity is almost complete by 5 years of age (4). These nonenveloped, triple-layered, doublestranded RNA viruses are members of the family Reoviridae (13). Their outer capsid is composed of the glycoprotein VP7, through which spikes of the protein VP4 protrude (45). Both VP4 and VP7 independently elicit neutralizing, protective antibodies and are serotype determinants (40). VP4 is an important determinant of virulence, host cell tropism (28), receptor binding, and cell penetration (31,35). Proteolytic cleavage by pancreatic trypsin of VP4 into two subunits, VP8‫ء‬ and VP5‫,ء‬ is required for virus infectivity and promotes rapid virus internalization into the cell. VP6 forms the capsid underlying the outer capsid and determines group and subgroup specificity (13).Rotaviruses normally infect the mature enterocytes of the small intestine but may spread extraintestinally. Indications of rotavirus infection of the liver in humans include elevated liver aminotransferase activity during rotavirus infection (17), rotavirus particles in a liver abscess (18), and rotavirus replication in HepG2 cells (32,52). In children with severe combined immunodeficiency (SCID) and chronic rotavirus infection, replicating rotavirus is present in the liver and kidneys and rotavirus antigen is detectable in the serum (16, 51).Severe rotavirus gastroenteritis has been associated with pancreatitis in two children (12, 39) and with nonketotic hyperglycemic syndrome in one child (48). Extraintestinal rotavirus detection in these children was not attempted. Pancreatic islet cell autoantibodies were detected in acute-phase but not convalescent-phase serum from one child (39). These antibodies are markers of islet autoimmunity and predict the T-cellmediated destruction of islet ␤ cells, leading to type 1 diabetes (T1D). In addition to islet cell autoantibodies, the subclinical autoimmune prodrome of T1D is characterized by circulating autoantibodies to insulin, glutamic acid decarboxylase (GAD), and tyrosine phosphatase-like islet antigen 2 (IA-2) (20). We detected autoantibodies to GAD and to IA-2 in acute-and/or convalescent-phase sera of 3 (30%) of 10 children without a family history of diabetes who were hospitalized with rotavirus gastroenteritis (24). This rate was at least four times that observed in normal schoolchildren (2).The strong en...