title: Molecular mechanisms of retroviral integration site selection.
abstract: Retroviral replication proceeds through an obligate integrated DNA provirus, making retroviral vectors attractive vehicles for human gene-therapy. Though most of the host cell genome is available for integration, the process of integration site selection is not random. Retroviruses differ in their choice of chromatin-associated features and also prefer particular nucleotide sequences at the point of insertion. Lentiviruses including HIV-1 preferentially integrate within the bodies of active genes, whereas the prototypical gammaretrovirus Moloney murine leukemia virus (MoMLV) favors strong enhancers and active gene promoter regions. Integration is catalyzed by the viral integrase protein, and recent research has demonstrated that HIV-1 and MoMLV targeting preferences are in large part guided by integrase-interacting host factors (LEDGF/p75 for HIV-1 and BET proteins for MoMLV) that tether viral intasomes to chromatin. In each case, the selectivity of epigenetic marks on histones recognized by the protein tether helps to determine the integration distribution. In contrast, nucleotide preferences at integration sites seem to be governed by the ability for the integrase protein to locally bend the DNA duplex for pairwise insertion of the viral DNA ends. We discuss approaches to alter integration site selection that could potentially improve the safety of retroviral vectors in the clinic.
authors.affiliation: Center for Retrovirus Research and College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA alan_engelman@dfci.harvard.edu.
authors.forename: Mamuka
authors.initials: M
authors.lastname: Kvaratskhelia
authors.affiliation: Center for Retrovirus Research and College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Amit
authors.initials: A
authors.lastname: Sharma
authors.affiliation: Center for Retrovirus Research and College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Ross C
authors.initials: RC
authors.lastname: Larue
authors.affiliation: Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute and Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Erik
authors.initials: E
authors.lastname: Serrao
authors.affiliation: Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute and Department of Medicine, Harvard Medical School, Boston, MA 02215, USA alan_engelman@dfci.harvard.edu.
authors.forename: Alan
authors.initials: A
authors.lastname: Engelman
mesh_terms: D015316:Genetic Therapy; D005822:Genetic Vectors; D015497:HIV-1 / Q000201:enzymology / Q000235:genetics / Q000502:physiology*; D006801:Humans; D019426:Integrases / Q000737:chemistry / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry / Q000378:metabolism; D008979:Moloney murine leukemia virus / Q000201:enzymology / Q000235:genetics / Q000502:physiology*; D016662:Virus Integration
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; C119380:lens epithelium-derived growth factor; D019426:Integrases