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 causing rabies disease, or the vesiculo-stomatitis G protein (VSV-G). Both envelopes induced syncitia in cell cultures. They were incorporated into vector particles and mature virions were observed by electron microscopy. Vector production 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-fold higher with VSV-G than with MK-G pseudotypes on cultured cells, and in vivo gene expression in mouse brain was more intense. Thus, VSV-G pseudotypes were produced more efficiently and were more infectious than MK-G pseudotypes. Tropism for brain cells was analyzed by intrastriatal injections in rats. Both pseudotypes preferentially transduced neurons (70-90% of transduced cells). Retrograde axonal transport was investigated by instilling vector suspensions in the rat nasal cavity. Both pseudotypes were efficiently transported to olfactive neuron bodies. Thus, although coating HIV-1 particles with rabdhovirus envelope glycoproteins enables them to enter neuronal cells efficiently, pseudotyping is not sufficient to confer the powerful neurotropism of lyssaviruses to lentivirus vectors.
Desmaris
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N
Unité Rétrovirus et Transfert Génétique, CNRS URA 1930, 28 Rue du Dr Roux, Paris, 75724, France.
Bosch
A
A
Salaün
C
C
Petit
C
C
Prévost
M C
MC
Tordo
N
N
Perrin
P
P
Schwartz
O
O
de Rocquigny
H
H
Heard
J M
JM
D000818:Animals; D001921:Brain / Q000166:cytology / Q000502:physiology* / Q000821:virology; D002460:Cell Line; D003342:Corpus Striatum; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D005966:Glucuronidase / Q000235:genetics / Q000378:metabolism; D015497:HIV-1 / Q000235:genetics* / Q000502:physiology; D006801:Humans; D007267:Injections; D018114:Lyssavirus / Q000235:genetics* / Q000502:physiology; D008562:Membrane Glycoproteins; D051379:Mice; D008856:Microscopy, Fluorescence; D009474:Neurons / Q000502:physiology; D051381:Rats; D014162:Transfection; D014759:Viral Envelope Proteins / Q000235:genetics* / Q000378:metabolism; D001616:beta-Galactosidase / Q000235:genetics / Q000378:metabolism
C028391:G protein, vesicular stomatitis virus; D008562:Membrane Glycoproteins; D014759:Viral Envelope Proteins; D001616:beta-Galactosidase; D005966:Glucuronidase