Sendai F/HN pseudotyped lentiviral vector transduces human ciliated and non-ciliated airway cells using α 2,3 sialylated receptors

A lentiviral vector (LV) pseudotype derived from the fusion (F) and hemagglutinin-neuraminidase (HN) glycoproteins of a murine respirovirus (Sendai virus) facilitates efficient targeting of murine lung in vivo. Since targeting of the human lung will depend upon the availability and distribution of receptors used by F/HN, we investigated transduction of primary human airway cells differentiated at the air-liquid interface (ALI). We observed targeting of human basal, ciliated, goblet, and club cells, and using a combination of sialidase enzymes and lectins, we showed that transduction is dependent on the availability of sialylated glycans, including a2,3 sialylated N-acetyllactosamine (LacNAc). Transduction via F/HN was 300-fold more efficient than another hemagglutinin-based LV pseudotype derived from influenza fowl plague virus (HA Rostock), despite similar efficiency reported in murine airways in vivo. Using specific glycans to inhibit hemagglutination, we showed this could be due to a greater affinity of F/HN for a2,3 sialylated LacNAc. Overall, these results highlight the importance of identifying the receptors used in animal and cell-culture models to predict performance in the human airways. Given the reported prevalence of a2,3 sialylated LacNAc on human pulmonary cells, these results support the suitability of the F/HN pseudotype for human lung gene therapy applications.