title: Enhanced pseudotyping efficiency of HIV-1 lentiviral vectors by a rabies/vesicular stomatitis virus chimeric envelope glycoprotein.
abstract: Rabies virus glycoprotein (RVG) can pseudotype lentiviral vectors, although at a lower efficiency to that of vesicular stomatitis virus glycoprotein (VSVG). Transduction with VSVG-pseudotyped vectors of rodent central nervous system (CNS) leads to local neurotropic gene transfer, whereas with RVG-pseudotyped vectors additional disperse transduction of neurons located at distal efferent sites occurs via axonal retrograde transport. Attempts to produce high-titre RVG-pseudotyped lentiviral vectors for preclinical and clinical trials has to date been problematic. We have constructed several chimeric RVG/VSVG glycoproteins and found that a construct bearing the external/transmembrane domain of RVG and the cytoplasmic domain of VSVG shows increased incorporation onto HIV-1 lentiviral particles and has increased infectivity in vitro in 293T cells and in differentiated neuronal cell lines of human, rat and murine origin. Stereotactic application of vector pseudotyped with this RVG/VSVG chimera in the rat striatum resulted in efficient gene transfer at the site of injection showing both neuronal and glial tropism. Distal neuronal transduction in the substantia nigra, thalamus and olfactory bulb via retrograde axonal transport also occurs after intrastriatal administration of chimera-pseudotyped vectors at similar levels to that observed with a RVG-pseudotyped vector. This is the first report of distal transduction in the olfactory bulb. The enhanced pseudotyping with this envelope should enable easier production of higher-titre pseudotyped lentiviral vectors that exhibit efficient local and dispersed neuronal transduction in the CNS.
authors: Department of Gene Therapy, Centre for Neurosciences, Division of Experimental Medicine, Faculty of Medicine, Imperial College London, Hammersmith Hospital, UK.
authors: D C J
authors: DC
authors: Carpentier
authors: K
authors: K
authors: Vevis
authors: A
authors: A
authors: Trabalza
authors: C
authors: C
authors: Georgiadis
authors: S M
authors: SM
authors: Ellison
authors: R I
authors: RI
authors: Asfahani
authors: N D
authors: ND
authors: Mazarakis
mesh_terms: D000956:Antigens, Viral / Q000235:genetics*; D005822:Genetic Vectors; D006023:Glycoproteins / Q000235:genetics*; D015497:HIV-1 / Q000235:genetics*; D008562:Membrane Glycoproteins / Q000235:genetics*; D014161:Transduction, Genetic; D014759:Viral Envelope Proteins / Q000235:genetics*
chemical_list: D000956:Antigens, Viral; C028391:G protein, vesicular stomatitis virus; D006023:Glycoproteins; D008562:Membrane Glycoproteins; D014759:Viral Envelope Proteins; C064951:glycoprotein G, Rabies virus