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A critical role for alternative polyadenylation factor CPSF6 in targeting HIV-1 integration to transcriptionally active chromatin.
Sowd, Gregory A; Serrao, Erik; Wang, Hao; Wang, Weifeng; Fadel, Hind J; Poeschla, Eric M; Engelman, Alan N.
Afiliação
  • Sowd GA; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215;
  • Serrao E; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215;
  • Wang H; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215;
  • Wang W; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215;
  • Fadel HJ; Division of Infectious Diseases, Department of Medicine, Mayo Clinic, Rochester, MN 55905;
  • Poeschla EM; Division of Infectious Diseases, University of Colorado School of Medicine, Denver, CO 80045.
  • Engelman AN; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215; alan_engelman@dfci.harvard.edu.
Proc Natl Acad Sci U S A ; 113(8): E1054-63, 2016 Feb 23.
Article em En | MEDLINE | ID: mdl-26858452
ABSTRACT
Integration is vital to retroviral replication and influences the establishment of the latent HIV reservoir. HIV-1 integration favors active genes, which is in part determined by the interaction between integrase and lens epithelium-derived growth factor (LEDGF)/p75. Because gene targeting remains significantly enriched, relative to random in LEDGF/p75 deficient cells, other host factors likely contribute to gene-tropic integration. Nucleoporins 153 and 358, which bind HIV-1 capsid, play comparatively minor roles in integration targeting, but the influence of another capsid binding protein, cleavage and polyadenylation specificity factor 6 (CPSF6), has not been reported. In this study we knocked down or knocked out CPSF6 in parallel or in tandem with LEDGF/p75. CPSF6 knockout changed viral infectivity kinetics, decreased proviral formation, and preferentially decreased integration into transcriptionally active genes, spliced genes, and regions of chromatin enriched in genes and activating histone modifications. LEDGF/p75 depletion by contrast preferentially altered positional integration targeting within gene bodies. Dual factor knockout reduced integration into genes to below the levels observed with either single knockout and revealed that CPSF6 played a more dominant role than LEDGF/p75 in directing integration to euchromatin. CPSF6 complementation rescued HIV-1 integration site distribution in CPSF6 knockout cells, but complementation with a capsid binding mutant of CPSF6 did not. We conclude that integration targeting proceeds via two distinct mechanisms capsid-CPSF6 binding directs HIV-1 to actively transcribed euchromatin, where the integrase-LEDGF/p75 interaction drives integration into gene bodies.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Cromatina / Capsídeo / HIV-1 / Integração Viral / Fatores de Poliadenilação e Clivagem de mRNA Limite: Humans Idioma: En Ano de publicação: 2016 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Cromatina / Capsídeo / HIV-1 / Integração Viral / Fatores de Poliadenilação e Clivagem de mRNA Limite: Humans Idioma: En Ano de publicação: 2016 Tipo de documento: Article