Human fibroblast growth factor receptor 1 is a co-receptor for infection by adeno-associated virus 2

Abstract

Adeno-associated virus 2 (AAV)-based vectors have gained attention as a potentially useful alternative to the more commonly used retroviral and adenoviral vectors for human gene therapy. Although AAV uses the ubiquitously expressed cell surface heparan sulfate proteoglycan (HSPG) as a receptor, the transduction efficiency of AAV vectors varies greatly in different cells and tissues in vitro and in vivo. We demonstrate here that cell surface expression of HSPG alone is insufficient for AAV infection, and that AAV also requires human fibroblast growth factor receptor 1 (FGFR1) as a co-receptor for successful viral entry into the host cell. We document that cells that do not express either HSPG or FGFR1 fail to bind AAV and, consequently, are resistant to infection by AAV. These non-permissive cells are successfully transduced by AAV vectors after stable transfections with cDNAs encoding the murine HSPG and the human FGFR1. Furthermore, AAV infection of permissive cells, known to express both FGFR1 and the epidermal growth factor receptor, is abrogated by treatment of cells with basic fibroblast growth factor, but not with epidermal growth factor. The identification of FGFR1 as a co-receptor for AAV should provide new insights not only into its role in the life cycle of AAV, but also in the optimal use of AAV vectors in human gene therapy.

A novel glioblastoma cancer gene therapy using AAV-mediated long-term expression of human TERT C-terminal polypeptide

“…Expression of hTERTC27 and EGFP in human glioblastoma U87-MG cells, respectively, infected with rAAV-hTERTC27 and rAAV-EGFP As AAV infection requires the presence of heparan sulfate proteoglycan and human fibroblast growth factor 1 as a co-receptor, 18 we first tested whether the packaged rAAVhTERTC27 and rAAV-EGFP can successfully infect the human glioblastoma U87-MG cells in vitro. The U87-MG cell line was chosen in this study, because it is one of the most tumorigenic glioblastoma cell lines identified to date.…”

Cellular tropism and transduction properties of seven adeno-associated viral vector serotypes in adult retina after intravitreal injection

“…21 AAV2 is known to enter cells through the heparin sulphate proteoglycan receptor, fibroblast growth factor receptor 1 and the integrin receptors aVb1 and aVb5. [44][45][46][47] A laminin receptor has also been implicated for AAV2 cell entry. 48 AAV6 can also bind to heparin sulphate proteoglycan receptors, 49,50 but unlike AAV2, AAV6 is not inhibited by soluble heparin.…”

Intracellular trafficking of adeno-associated viral vectors

“…Two coreceptors for AAV2 have thus far been identified. These include aVb5 integrin 50 and fibroblast growth 51 The level of aVb5 integrin expression can significantly influence the efficiency of rAAV2 transduction in certain cell types; however, its functions as a coreceptor has been debated. 52,53 Nonetheless, inhibition of aVb5 integrin with blocking antibodies can prevent internalization of bound rAAV2 on the surface of HeLa cells.…”