Tropism, intracerebral distribution, and transduction efficiency of HIV- and SIV-based lentiviral vectors after injection into the mouse brain: a qualitative and quantitative in vivo study

Abstract

Lentiviruses are suitable to transfer potential therapeutic genes into non-replicating cells such as neurons, but systematic in vivo studies on transduction of neural cells within the complete brain are missing. We analysed the distribution of transduced cells with respect to brain structure, virus tropism, numbers of transduced neurons per brain, and influence of the Vpx or Vpr accessory proteins after injection of vectors based on SIVsmmPBj, HIV-2, and HIV-1 lentiviruses into the right striatum of the mouse brain. Transduced cells were found ipsilaterally around the injection canal, in corpus striatum and along corpus callosum, irrespective of the vector type. All vectors except HIV-2SEW transduced also single cells in the olfactory bulb, hippocampus, and cerebellum. Vector HIV-2SEW was the most neuron specific. However, vectors PBjSEW and HIV-1SEW transduced more neurons per brain (means 41,299 and 32,309) than HIV-2SEW (16,102). In the presence of Vpx/Vpr proteins, HIV-2SEW(Vpx) and HIV-1SEW(Vpr) showed higher overall transduction efficiencies (30,696 and 27,947 neurons per brain) than PBjSEW(Vpx) (6636). The distances of transduced cells from the injection canal did not differ among the viruses but correlated positively with the numbers of transduced neurons. The presence of Vpx/Vpr did not increase the numbers of transduced neurons. Parental virus type and the vector equipment seem to influence cellular tropism and transduction efficiency. Thus, precision of injection and choice of virus pseudotype are not sufficient when targeted lentiviral vector transduction of a defined brain cell population is required.Electronic supplementary materialThe online version of this article (doi:10.1007/s00418-017-1569-1) contains supplementary material, which is available to authorized users.

Using virtual microscopy for the development of sampling strategies in quantitative histology and design‐based stereology

“…Brains of female C57B1/6 mice (C) Tracking the transduction of various viral vectors in neurons after being injected into mice brains (Hlavatý et al, 2017).…”

Gene Therapy Applications of Non-Human Lentiviral Vectors

“…Furthermore, although researchers have sought to remove accessory viral proteins from LV systems due to biosafety concerns, it has been demonstrated that LV tropism and efficacy can be altered by the inclusion of vpx . In in vivo studies in mice and rats, SIV-based LVs lacking accessory proteins have demonstrated robust tropism towards neurons [ 95 , 102 ]; however, Hlavaty and colleagues were able to modify the vector to preferentially target glial cells in mice via the introduction of the vpx gene in the packaging construct [ 102 ]. In addition, the accessory Vpx protein has been exploited to manipulate the early phases of lentiviral infection.…”