A small-molecule-controlled system for efficient pseudotyping of prototype foamy virus vectors

Abstract

Foamy virus (FV) vector systems have recently demonstrated their power as efficient gene transfer tools for different target tissues. Unfortunately, FVs cannot be naturally pseudotyped by heterologous viral glycoproteins due to an unusual particle morphogenesis involving a FV Env-dependent particle release process. Therefore, current FV vector systems are constrained to the broad host cell range provided by the cognate viral glycoprotein. We evaluated different approaches for pseudotyping of FV vectors, in which the specific FV Gag-Env interaction, essential for particle egress, is substituted by a small-molecule controlled heterodimerization (HD) system. In one system developed, one HD-domain (HDD) is fused to a membrane-targeting domain (MTD), such as the human immunodeficiency virus (HIV) Gag matrix (MA) subunit, with a second fused to the FV capsid protein. Coexpression of both components with different heterologous viral glycoproteins allowed an efficient, dimerizer-dependent pseudotyping of FV capsids. With this system FV vesicular stomatitis virus glycoprotein (VSV-G) pseudotype titers greater than 1 × 106 IU/ml were obtained, at levels comparable to authentic FV vector particles. As a proof-of-principle we demonstrate that Pac2 cells, naturally resistant to FV vectors, become permissive to FV VSV-G pseudotypes. Similar to other retroviral vectors, this FV pseudotyping system now enables adaptation of cell-specific targeting approaches for FVs. © The American Society of Gene & Cell Therapy.