Date of Award
hepatitis C virus, bovine viral diarrhea virus, flaviviridae
Hepatitis C virus (HCV) and bovine viral diarrhea virus (BVDV) are closely related members of the family Flaviviridae and are important human and animal pathogens, respectively. In this work, I investigated how these viruses interact with and enter both naÃ¯ve and previously infected cells, specifically, the mechanisms of superinfection exclusion, the phenomenon by which previous viral infection prevents reinfection of the same cell, and the pathways of entry into target cells for these viruses. BVDV-acutely infected cells establish two blocks to superinfection, at the levels of virus entry and RNA replication. The former is mediated by the BVDV E2 protein, which was also identified as a transdominant inhibitor of BVDV entry in a screen of a random fragment BVDV cDNA library. The inhibitory region was further mapped to the E2 ectodomain and the block to entry was shown to occur downstream of CD46 receptor expression and BVDV binding, suggesting interference with a yet unidentified BVDV entry factor. In contrast to BVDV, HCV-infected and replicon-containing cells exhibit a post-entry block to superinfection, at one or more steps in viral replication. The entry pathways of both BVDV and HCV into target cells were also examined and found to be pH-dependent. In addition, these viruses were shown to be very acid-resistant, suggesting that they require an activation step to trigger pH-dependent entry. The role of the cellular receptors/coreceptors, CD81, scavenger receptor class B type 1 (SR-BI), and claudin-1 (CLDN1), in mediating HCV entry and their modulation during persistent HCV replication were also investigated. This work highlights common features shared between BVDV and HCV and provides insight into the cellular environment required for productive virus entry and RNA replication.
Tscherne, Donna M., "Dissecting the Entry Pathways of Hepatitis C and Bovine Viral Diarrhea Viruses" (2007). Student Theses and Dissertations. 17.