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

Area of Science:

• Gene Therapy
• Virology
• Molecular Biology

Background:

• Foamy virus (FV) vectors are potent gene transfer tools but are limited by their inability to incorporate foreign viral glycoproteins.
• This limitation stems from an FV Env-dependent particle release mechanism, restricting FV vectors to the host range of their native glycoprotein.

Purpose of the Study:

• To develop a novel method for pseudotyping FV vectors with heterologous viral glycoproteins.
• To overcome the inherent limitations of FV vector host cell range and enable adaptable targeting strategies.

Main Methods:

• A small-molecule controlled heterodimerization (HD) system was engineered to replace the natural FV Gag-Env interaction required for particle release.
• One HD-domain was fused to a membrane-targeting domain (e.g., HIV Gag matrix), and the other to the FV capsid protein.
• Coexpression of these components with heterologous viral glycoproteins facilitated dimerizer-dependent FV capsid pseudotyping.

Main Results:

• The engineered HD system enabled efficient, dimerizer-dependent pseudotyping of FV vectors.
• FV vectors pseudotyped with vesicular stomatitis virus glycoprotein (VSV-G) achieved titers exceeding 1 × 10(6) IU/ml, comparable to native FV vectors.
• Naturally FV-resistant Pac2 cells became susceptible to FV VSV-G pseudotypes, demonstrating successful pseudotyping and altered tropism.

Conclusions:

• A novel heterodimerization system successfully enables pseudotyping of FV vectors with heterologous glycoproteins.
• This technology overcomes FV vector tropism limitations, allowing for tailored gene delivery to specific cell types.
• The developed FV pseudotyping system holds significant promise for advancing cell-specific gene therapy applications.