Adeno-associated viruses (AAVs) use a variety of cellular receptors/coreceptors to gain entry into cells. A number of AAV serotypes are now available, and the cognate receptors/coreceptors for only a handful of those have been identified thus far. Of the 10 commonly used AAV serotypes, AAV3 is by far the least efficient in transducing cells in general. However, in our more recent studies, we observed that AAV3 vectors transduced human liver cancer cells remarkably well, which led to the hypothesis that AAV3 uses hepatocyte growth factor receptor (HGFR) as a cellular coreceptor for viral entry. AAV3 infection of human liver cancer cell lines was strongly inhibited by hepatocyte growth factor, HGFR-specific small interfering RNA, and anti-HGFR antibody, which corroborated this hypothesis. However, AAV3 vectors failed to transduce murine hepatocytes, both in vitro and in vivo, suggesting that AAV3 specifically uses human HGFR, but not murine HGFR, as a cellular coreceptor for transduction. AAV3 may prove to be a useful vector for targeting human liver cancers for the potential gene therapy.
We investigated the performance of AST to platelet ratio index (APRI) as a non-invasive marker of fibrosis and cirrhosis in children with chronic viral hepatitis. All patients 0–20 years old with chronic hepatitis B or C seen at a tertiary medical center from 1992–2008 were identified. 36 patients were evaluated with 48 biopsy results. The areas under the ROC curve were 0.71 for fibrosis and 0.52 for cirrhosis. When examining subgroups, the APRI performed better in older patients and in those with vertically transmitted HCV. Further research into APRI and other non-invasive markers of fibrosis in children with chronic viral hepatitis is warranted.
Our recent studies have revealed that among the 10 different commonly used AAV serotypes, AAV3 vectors transduce human liver cancer cells extremely efficiently because these cells express high levels of human hepatocyte growth factor receptor (hHGFR), and AAV3 utilizes hHGFR as a cellular co-receptor for viral entry. In this report, we provide further evidence that both extracellular as well as intracellular kinase domains of hHGFR are involved in AAV3 vector entry and AAV3-mediated transgene expression. We also document that AAV3 vectors are targeted for degradation by the host cell proteasome machinery, and that site-directed mutagenesis of surface exposed tyrosine (Y) to phenylalanine (F) residues on AAV3 capsids significantly improves the transduction efficiency of Y701F, Y705F and Y731F mutant AAV3 vectors. The transduction efficiency of the Y705+731F double-mutant vector is significantly higher than each of the single-mutants in liver cancer cells in vitro. In immuno-deficient mouse xenograft models, direct intra-tumor injection of AAV3 vectors also led to high-efficiency transduction of human liver tumor cells in vivo. We also document here that the optimized tyrosine-mutant AAV3 vectors lead to increased transduction efficiency following both intra-tumor and tail-vein injections in vivo. The optimized tyrosine-mutant AAV3 serotype vectors containing pro-apoptotic genes should prove useful for the potential gene therapy of human liver cancers.
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