Production and neurotropism of lentivirus vectors pseudotyped with lyssavirus envelope glycoproteins

We investigated the production efficiency and the gene transfer capacity in the central nervous system of HIV-1-based vectors pseudotyped with either the G protein of the Mokola lyssaviruses (MK-G), a neurotropic virus causin g rabies disease, or the vesiculo-stomatitis G protein (VSV-G). Both envelo pes induced syncitia in cell cultures. They were incorporated into vector p articles and mature virions were observed by electron microscopy. Vector pr oduction was two- to sixfold more efficient with VSV-G than with MK-G. For equivalent amounts of physical particles, vector titration was 5- to 25-fol d higher with VSV-G than with MK-G pseudotypes on cultured cells, and in vi vo gene expression in mouse brain was more intense. Thus, VSV-G pseudotypes were produced more efficiently and were more infectious than MK-G pseudoty pes. Tropism for brain cells was analyzed by intrastriatal injections in ra ts. Both pseudotypes preferentially transduced neurons (70-90% of transduce d cells). Retrograde axonal transport was investigated by instilling vector suspensions in the rat nasal cavity. Both pseudotypes were efficiently tra nsported to olfactive neuron bodies. Thus, although coating HIV-1 particles with rabdhovirus envelope glycoproteins enables them to enter neuronal cel ls efficiently, pseudotyping is not sufficient to confer the powerful neuro tropism of lyssaviruses to lentivirus vectors.