Integration site selection by lentiviruses: biology and possible control.
Retroviruses integrate into naked DNA in a generally sequence nonspecific fashion, but closer study reveals a variety of forces that influence target site selection. Primary sequence of the target plays a small but detectable role. Proteins bound to target DNA can inhibit integration by blocking access of integration complexes or stimulate integration by distorting DNA. An important example of the latter is DNA distortion in nucleosomal DNA. In vivo integration has not yet been convincingly shown to be biased in favor of any identifiable sequence features, though this could still change in future studies. Many applications of retroviral vectors could be facilitated by targeting integration in vivo to predetermined sites. Towards this end, several groups have studied the properties of fusions of integrase proteins to sequence-specific DNA-binding domains. To date such studies establish that targeting can work well in reactions in vitro, but a variety of obstacles complicate applications in vivo. However, naturally occurring retrotransposons do carry out highly targeted integration using retrovirus-like integrase proteins, fueling long-term hopes for targeting with retroviral integrases as well.
Bushman
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Infectious Disease Laboratory, Salk Institute, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
D004279:DNA, Viral / Q000235:genetics; D018390:Gene Targeting; D015316:Genetic Therapy / Q000009:adverse effects; D005822:Genetic Vectors / Q000009:adverse effects; D015497:HIV-1 / Q000235:genetics; D006801:Humans; D016086:Lentivirus / Q000235:genetics*; D018626:Retroelements / Q000235:genetics; D012190:Retroviridae / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000235:genetics; D016662:Virus Integration / Q000235:genetics
D004279:DNA, Viral; D018626:Retroelements