TY - JOUR
T1 - Functional coupling between HIV-1 integrase and the SWI/SNF chromatin remodeling complex for efficient in vitro integration into stable nucleosomes
AU - Lesbats, Paul
AU - Botbol, Yair
AU - Chevereau, Guillaume
AU - Vaillant, Cédric
AU - Calmels, Christina
AU - Arneodo, Alain
AU - Andreola, Marie Line
AU - Lavigne, Marc
AU - Parissi, Vincent
N1 - Funding Information:
The authors are deeply grateful to Dr Simon Litvak for fruitful discussions and constant encouragement and to Prof. R. Cooke (University Victor Segalen Bordeaux 2) for proofreading the manuscript. We also thank S. Garbay (Institut Cochin, Paris, France) for his help in the recovery of published integration sites, P. Cherepanov (Imperial College, London, England) and A. Engelman (Harvard University, Boston, USA) for fruitful discussions about intasome and nucleosomes and G. Narlikar (UCSF, USA) for providing us with biological materials and discussions about chromatin remodeling. We also thank the French National Research Agency against AIDS (ANRS), the Centre National de la Recherche Scientifique (CNRS), the University Victor Segalen Bordeaux 2 and the French Research Group GDR 2157 “Transposable Elements” for supporting this project.
PY - 2011/2
Y1 - 2011/2
N2 - Establishment of stable HIV-1 infection requires the efficient integration of the retroviral genome into the host DNA. The molecular mechanism underlying the control of this process by the chromatin structure has not yet been elucidated. We show here that stably associated nucleosomes strongly inhibit in vitro two viral-end integration by decreasing the accessibility of DNA to integrase. Remodeling of the chromatinized template by the SWI/SNF complex, whose INI1 major component interacts with IN, restores and redirects the full-site integration into the stable nucleosome region. These effects are not observed after remodeling by other human remodeling factors such as SNF2H or BRG1 lacking the integrase binding protein INI1. This suggests that the restoration process depends on the direct interaction between IN and the whole SWI/SNF complex, supporting a functional coupling between the remodeling and integration complexes. Furthermore, in silico comparison between more than 40,000 non-redundant cellular integration sites selected from literature and nucleosome occupancy predictions also supports that HIV-1 integration is promoted in the genomic region of weaker intrinsic nucleosome density in the infected cell. Our data indicate that some chromatin structures can be refractory for integration and that coupling between nucleosome remodeling and HIV-1 integration is required to overcome this natural barrier.
AB - Establishment of stable HIV-1 infection requires the efficient integration of the retroviral genome into the host DNA. The molecular mechanism underlying the control of this process by the chromatin structure has not yet been elucidated. We show here that stably associated nucleosomes strongly inhibit in vitro two viral-end integration by decreasing the accessibility of DNA to integrase. Remodeling of the chromatinized template by the SWI/SNF complex, whose INI1 major component interacts with IN, restores and redirects the full-site integration into the stable nucleosome region. These effects are not observed after remodeling by other human remodeling factors such as SNF2H or BRG1 lacking the integrase binding protein INI1. This suggests that the restoration process depends on the direct interaction between IN and the whole SWI/SNF complex, supporting a functional coupling between the remodeling and integration complexes. Furthermore, in silico comparison between more than 40,000 non-redundant cellular integration sites selected from literature and nucleosome occupancy predictions also supports that HIV-1 integration is promoted in the genomic region of weaker intrinsic nucleosome density in the infected cell. Our data indicate that some chromatin structures can be refractory for integration and that coupling between nucleosome remodeling and HIV-1 integration is required to overcome this natural barrier.
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U2 - 10.1371/journal.ppat.1001280
DO - 10.1371/journal.ppat.1001280
M3 - Article
C2 - 21347347
AN - SCOPUS:79952205472
SN - 1553-7366
VL - 7
JO - PLoS pathogens
JF - PLoS pathogens
IS - 2
M1 - e1001280
ER -