Cellular Protrusions Engage Viral Infection Enhancing EF-C Peptide Nanofibrils

Self-assembling peptide nanofibrils (PNF) have gained increasing attention as versatile molecules in material science and biomedicine. One important application of PNF is to enhance retroviral gene transfer, a technology that has been central to the development of gene therapy. The best-investigated and commercially available PNF is derived from a 12-mer peptide termed EF-C. The mechanism of transduction enhancement depends on the polycationic surface of EF-C PNF, which binds to the negatively charged membranes of viruses and cells thereby overcoming electrostatic repulsion and increasing virion attachment and fusion. Assuming an even distribution of charges at the surfaces of virions and cells would result in an evenly distributed interaction of the virions with the cell surface. However, we here report that PNF do not randomly bind at the cell surface but are actively engaged by cellular protrusions. Chemical suppression of protrusion formation in cell lines and primary CD4+ T cells greatly reduced fibril binding and hence virion binding. Thus, the mechanism of PNF-mediated viral transduction enhancement involves active engagement of virus-loaded fibrils by cellular protrusions.