Lentiviral vectors based on human immunodeficiency virus type 1 (HIV-1) have been used not only for various basic research experiments, but also for a wide range of gene therapy trials in animal models. The development of a pseudotyped lentiviral vector with the property of retrograde infection allows us to introduce foreign genes into neuronal cell bodies that are localized in regions innervating the site of vector injection. This enables pathway-selective gene manipulation in the primate brain. Recently, it has been demonstrated that the use of a novel type of fusion glycoprotein (FuG-E) of which segmental junction was optimized results in increased retrograde gene transfer relative to the parental fusion glycoprotein (FuG-C) in mice.
Here, we report the efficiency of retrograde gene transfer of the FuG-E pseudotyped vector in the primate brain by comparing its transduction pattern with the pattern induced by the parental FuG-C pseudotyped vector. After injection of the FuG-E vector encoding GFP (4.5 x 10⁹ genome copies) into the striatum of macaque monkeys, many GFP-positive neurons were located in regions innervating the striatum, such as the cerebral cortex, thalamus and substantia nigra. Quantitative analysis revealed that the number of neurons retrogradely transduced with the FuG-E vector was approximately 2.2, 2.0, or 1.2 times higher than the FuG-C vector in the primary motor cortex, CM-Pf thalamic nucleus, or substantia nigra pars compacta, respectively. We also confirmed that the FuG-E vector displays explicit neuron specificity to the same extent as the FuG-C vector. The present results indicate that pseudotyping of the HIV-1-based vector with FuG-E glycoprotein largely enhances the efficiency of gene transfer through retrograde axonal transport in the primate brain. This vector might promote an approach to pathway-selective gene manipulation and provide a powerful tool for effective gene therapeutic trials against neurological disorders through enhanced retrograde delivery.

研究助成：Research funds : KAKENHI(15H01431) to K.I. and KAKENHI(25250003) to M.T.