The present invention provides an integration-defective lentiviral vector based on a parental
lentivirus and related methods, the integration-defective lentiviral vector including one or more of the following: (a) a
mutation, deletion or other modification of one or more binding sites for a
host factor involved in
gene silencing; (b) an addition of one or more binding sites for a transcription activator, which can be natural (such as but not limited to ubiquitous and / or tissue /
cell type specific) including but not limited to SP1 NFkB, or synthetic including but not limited to binding sites for
tetracycline regulated trans activators tTA, rtTA, tT65, and / or rtT65; (c) one or more
nucleic acid sequences from a SV40
genome, wherein the one or more sequences are obtained from a region of the SV40
genome upstream to the SV40 poly-adenylation
signal; (d) a shRNA
expression cassette, which encodes a shRNA directed to a
host gene involved in epigenetic silencing and / or in
DNA repair pathways; or (e) any combination of (a), (b), (c) and (d), wherein as compared to the parental
lentivirus, the integration-defective lentiviral vector resists
gene silencing.