Similarly to retroviral vectors, the design of lentiviral vector packaging systems has evolved to minimize the risk of RCPs generation towards maximum safety. Currently, three generations of lentiviral vectors are considered. The first-generation (Naldini et al. 1996) closely resembles the three plasmid packaging system of simple retroviruses, except for the fact that the gag-pol expression is driven by a heterologous promoter instead of the viral LTR; additionally, the gp120 HIV-1’s envelope was replaced by VSV-G’s. However, this system contained all the necessary sequences for the generation of RCPs with three homologous recombination events which, although improbable, could not be accepted for a human and potentially lethal pathogen
