Retroviral DNA integration: HIV and the role of LEDGF/p75.
To replicate, a retrovirus must integrate a DNA copy of its RNA genome into a chromosome of the host cell. Integration is not random in the host genome but favors particular regions, and preferences differ among retroviruses. Several mechanisms might play a part in this favored integration targeting: (i) open chromatin might be preferentially accessible for viral DNA integration; (ii) DNA replication during cell division might facilitate access of integration complexes to favored sites; and (iii) cellular proteins bound to the host chromosome might tether integration complexes to favored regions. This review summarizes recent advances in understanding the mechanisms of retroviral integration, focusing on LEDGF/p75--the first cellular protein shown to have a role in directing HIV DNA integration. Studies on LEDGF/p75 indicate that it directs HIV integration site selection by a tethering interaction, whereas the chromatin accessibility or cell cycle models are less well supported. Understanding viral integration will help improve the safety of retrovirus-based vectors used in gene therapy.
Ciuffi
Angela
A
University of Pennsylvania School of Medicine, Department of Microbiology, 3610 Hamilton Walk, Philadelphia, PA 19104-6076, USA. aciuffi@mail.med.upenn.edu
Bushman
Frederic D
FD
D002843:Chromatin / Q000378:metabolism; D004279:DNA, Viral / Q000502:physiology*; D006678:HIV / Q000502:physiology*; D015658:HIV Infections / Q000378:metabolism / Q000821:virology; D006801:Humans; D019426:Integrases / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology*; D016662:Virus Integration / Q000502:physiology*; D014779:Virus Replication
D002843:Chromatin; D004279:DNA, Viral; D036341:Intercellular Signaling Peptides and Proteins; C119380:lens epithelium-derived growth factor; D019426:Integrases