Silencing and variegation of gammaretrovirus and lentivirus vectors

Retrovirus vectors integrate into the genome, providing stable gene transfer, but integration contributes in part to transcriptional silencing that compromises long-term expression. In the case of gammaretrovirus vectors based on murine leukemia virus, many integration events are completely silenced in undifferentiated stem cells and in transgenic mice. Gammaretrovirus vectors are also subject to variegation in which sister cells bearing the same provirus differentially express, and cell differentiation can lead to extinction of vector expression. In contrast, lentivirus vectors based on human immunodeficiency virus type 1 appear to express more efficiently, although other reports indicate that lentivirus vectors can be silenced. This review summarizes the key features of gammaretrovirus vector silencing. The evidence for and against gene silencing of lentivirus vectors is described with special emphasis on the potential effects of vector design, provirus copy number, and integration site preferences on silencing. This analysis suggests that the difference between selfinactivating (SIN) lentivirus vectors and their modified SIN gammaretrovirus counterparts may be less dramatic than previously thought. It will therefore be important to further characterize the mechanisms of silencing, in order to create better gammaretrovirus and lentivirus vectors that consistently express at single copy for gene therapy.