title: Differential effects of human immunodeficiency virus type 1 capsid and cellular factors nucleoporin 153 and LEDGF/p75 on the efficiency and specificity of viral DNA integration.
abstract: Retroviruses integrate into cellular DNA nonrandomly. Lentiviruses such as human immunodeficiency virus type 1 (HIV-1) favor the bodies of active genes and gene-enriched transcriptionally active regions of chromosomes. The interaction between lentiviral integrase and the cellular protein lens epithelium-derived growth factor (LEDGF)/p75 underlies the targeting of gene bodies, whereas recent research has highlighted roles for the HIV-1 capsid (CA) protein and cellular factors implicated in viral nuclear import, including transportin 3 (TNPO3) and nucleoporin 358 (NUP358), in the targeting of gene-dense regions of chromosomes. Here, we show that CA mutations, which include the substitution of Asp for Asn74 (N74D), significantly reduce the dependency of HIV-1 on LEDGF/p75 during infection and that this difference correlates with the efficiency of viral DNA integration. The distribution of integration sites mapped by Illumina sequencing confirms that the N74D mutation reduces integration into gene-rich regions of chromosomes and gene bodies and reveals previously unrecognized roles for NUP153 (another HIV-1 cofactor implicated in viral nuclear import) and LEDGF/p75 in the targeting of the viral preintegration complex to gene-dense regions of chromatin. A role for the CA protein in determining the dependency of HIV-1 on LEDGF/p75 during infection highlights a connection between the viral capsid and chromosomal DNA integration.
authors.affiliation: Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Koh
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Wu
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Ferris
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Matreyek
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Smith
authors.forename: KyeongEun
authors.initials: K
authors.lastname: Lee
authors.forename: Vineet N
authors.initials: VN
authors.lastname: KewalRamani
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Hughes
authors.forename: Alan
authors.initials: A
authors.lastname: Engelman
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D036022:Capsid Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004279:DNA, Viral / Q000378:metabolism*; D015497:HIV-1 / Q000472:pathogenicity*; D054884:Host-Pathogen Interactions; D006801:Humans; D051379:Mice; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D020125:Mutation, Missense; D028861:Nuclear Pore Complex Proteins / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D016662:Virus Integration
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D036022:Capsid Proteins; D004279:DNA, Viral; D050505:Mutant Proteins; C079377:NUP153 protein, human; D028861:Nuclear Pore Complex Proteins; C504649:PSIP1 protein, human; D014157:Transcription Factors