Hepatitis A virus (HAV), a picornavirus, is the causative agent of acute hepatitis. Like other picornaviruses, HAV is assumed to enter the cell by first binding to a specific cellular receptor. Interaction of HAV with its cellular receptor could be responsible for many characteristics of HAV such as growth restriction in primate cells and hepatovirulence. Therefore, study of the interaction of HAV with its cellular receptor will help to understand the mechanisms involved in the pathogenicity of this virus and specific receptor antagonists could be useful therapeutic agents. Furthermore, identification of the HAV cellular receptor may lead to the development of small animal models for HAV infection. Such a model would be important for the testing of potency of future HAV vaccines. Monoclonal antibody (MAb) 190/4 directed against the surface of primary AGMK cells which protected cells against infection with HAV was used as a probe to molecularly clone the cellular receptor for HAV. Several nonprimate cells lines that could not be infected directly with HAV have now been infected after they were first transfected with the cDNA coding for the putative receptor. Sequence analysis of the HAV cellular receptor (HAVcr-1) cDNA revealed that it coded for a novel glycoprotein. Northern and Southern blotting has shown that humans have a related gene that is expressed in a variety of organs including liver. It has not been determined yet if this related protein also functions as a receptor for HAV. Transgenic mice that express the HAVcr-1 cDNA under the control of the RSV LTR promoter were developed. As expected, the HAVcr-1 transcripts are expressed in all organs of the transgenic animals. Transgenic mice were recently inoculated with wild type and attenuated HAV to analyze whether expression of HAVcr-1 is a determinant of pathogenesis of HAV. We hope to create a small animal model for HAV that would be useful for vaccine development and evaluation as well as pathogenesis studies.