Low-density lipoproteins in human serum competitively inhibit the binding and entry of vesicular stomatitis virus.

Vesicular stomatitis virus (VSV) is a promising anticancer agent but rapidly loses its infectivity in human serum. Here, we demonstrate that low-density and very low-density lipoproteins (LDLs and VLDLs) compete with VSV-G-displaying vectors for occupancy of cellular LDL receptors (LDLRs). Infectivity of VSV-G-displaying vectors was reduced two- to three-logs in the presence of heat-inactivated human serum but not if the serum was depleted of lipoproteins. The inhibitory effect was replicated in serum-free media supplemented with physiological concentrations of purified lipoprotein particles that contain the LDLR-binding protein Apo B-100, and the degree of inhibition correlated with the concentration of LDL or VLDL. When VSV-G was retargeted to the epidermal growth factor receptor, competitive inhibition by human serum or by LDL/VLDL was no longer observed. Similar results were obtained when VSV-G was retargeted to other receptors. Our findings demonstrate that serum LDL and VLDL competitively block the entry of VSV-G-displaying viral particles, but this barrier for in vivo delivery can be circumvented through a display of a receptor-targeting ligand on VSV-G.