Interaction between mouse adenovirus type 1 and cell surface heparan sulfate proteoglycans

Area of Science:

• Virology
• Gene Therapy
• Oncology

Background:

• Human adenovirus type 5 (Ad5) vectors for cancer gene therapy face limitations due to poor coxsackie-adenovirus-receptor (CAR) expression on some tumors.
• Ad5 accumulation in the liver is mediated by factor X (FX) binding and subsequent interaction with heparan sulfate proteoglycans (HSPGs).
• Mouse adenovirus type 1 (MAV-1) is an alternative vector with endothelial cell tropism that does not rely on CAR.

Purpose of the Study:

• To investigate the cellular attachment mechanisms of MAV-1.
• To compare MAV-1's receptor usage with that of Ad5.
• To evaluate MAV-1's potential as a gene therapy vector for human cancers.

Main Methods:

• Direct binding assays of MAV-1 and Ad5 to heparan sulfate-coated plates.
• Experiments using modified heparins to assess MAV-1's interaction with HSPGs.
• Slot blot assays to evaluate MAV-1's interaction with FX.
• Analysis of MAV-1 and Ad5 binding to the NCI-60 panel of human tumor cell lines.

Main Results:

• MAV-1 primarily uses cell surface HSPGs as its attachment receptor, showing more efficient binding than Ad5.
• MAV-1's HSPG interaction is dependent on N-sulfation and, to a lesser extent, 6-O-sulfation.
• Unlike Ad5, MAV-1's HSPG interaction is not enhanced by FX, although MAV-1 can bind FX, albeit at lower levels.
• MAV-1 preferentially binds to ovarian carcinoma cells within the NCI-60 panel.

Conclusions:

• MAV-1 utilizes HSPGs as its primary attachment receptor, with specific sulfation patterns influencing binding.
• MAV-1 exhibits distinct interaction properties with FX compared to Ad5, potentially reducing liver accumulation.
• MAV-1's tropism for ovarian cancer cells supports its development as a targeted gene therapy vector.