Hepatitis A virus (HAV) and hepatitis E virus (HEV) infections are common causes of epidemic food-borne and water-borne hepatitis in under-developed regions of the world. Recently sporadic HEV infections have emerged as a significant public health hazard in well-developed countries. The recognition of zoonotic and blood-borne HEV transmission and its ability to persistent in immunosuppressed individuals is also alarming. Approximately 20% of the U.S. population is seropositive for HEV, indicating that HEV exposure is more common than previously thought. Although both recognized as non-enveloped viruses, recent studies show that HAV and HEV circulate in the blood as quasi-enveloped particles. These novel particles differ from classic enveloped viruses in that no viral antigens are present on the surface of their membrane, therefore are highly resistant to neutralizing antibodies. The impact of this quasi-envelopment on hepatitis virus life cycle, immunity, and pathogenesis is poorly understood. This proposal will explore the mechanisms by which quasi- enveloped HAV and HEV enter the cells and are neutralized by antibodies. Aim 1 will test the hypothesis that entry of quasi-enveloped HAV and HEV is through a cellular mechanism for extracellular vesicular uptake. Aim 2 will determine the mechanism of neutralization for quasi-enveloped HAV and HEV. Completion of these aims will address several of the most significant gaps in our understanding of the quasi-enveloped virus life cycle and pathogenesis.