Human hepatocyte growth factor receptor is a cellular coreceptor for adeno-associated virus serotype 3

Parts used

Key findings

• Identified hHGFR as AAV3's specific co-receptor, establishing why AAV3 efficiently transduces human hepatocytes despite poor performance in mouse models. Critical for understanding species-specific tropism.

Abstract

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. Ling et al. identify human hepatocyte growth factor (hHGFR) as a novel receptor/coreceptor necessary for AAV3 entry into liver-specific cells. Using a variety of methods, the authors show that interference with the cell surface expression of HGFR significantly reduces the transduction efficiency of AAV3 vectors. Subsequent in vitro and in vivo experiments revealed that AAV3 specifically utilizes human HGFR (hHGFR), and not mouse HGFR (mHGFR).