Capsid-CPSF6 Interaction Licenses Nuclear HIV-1 Trafficking to Sites of Viral DNA Integration

被引:157
作者
Achuthan, Vasudevan [1 ,2 ]
Perreira, Jill M. [3 ]
Sowd, Gregory A. [1 ,2 ]
Puray-Chavez, Maritza [4 ]
McDougall, William M. [3 ]
Paulucci-Holthauzen, Adriana [5 ]
Wu, Xiaolin [6 ]
Fadel, Hind J. [7 ]
Poeschla, Eric M. [8 ]
Multani, Asha S. [5 ]
Hughes, Stephen H. [9 ]
Sarafianos, Stefan G. [4 ,11 ]
Brass, Abraham L. [3 ,10 ]
Engelman, Alan N. [1 ,2 ]
机构
[1] Dana Farber Canc Inst, Dept Canc Immunol & Virol, Boston, MA 02215 USA
[2] Harvard Med Sch, Dept Med, Boston, MA 02115 USA
[3] Univ Massachusetts, Sch Med, Dept Microbiol & Physiol Syst, Worcester, MA 01655 USA
[4] Univ Missouri, Sch Med, Dept Mol Microbiol & Immunol, Columbia, MO 65212 USA
[5] Univ Texas MD Anderson Canc Ctr, Dept Genet, Houston, TX 77030 USA
[6] Leidos Biomed Res Inc, Frederick, MD 21702 USA
[7] Mayo Clin, Div Mol Med, Rochester, MN 55905 USA
[8] Univ Colorado Denver, Sch Med, Div Infect Dis, Aurora, CO 80045 USA
[9] NCI, HIV Dynam & Replicat Program, Frederick, MD 21702 USA
[10] Univ Massachusetts, Sch Med, Dept Med, Div Gastroenterol, Worcester, MA 01655 USA
[11] Emory Univ, Sch Med, Dept Pediat, Atlanta, GA 30332 USA
关键词
ORDER CHROMATIN ARRANGEMENTS; WILD-TYPE LEVELS; HUMAN-CELLS; LAMINA INTERACTIONS; HUMAN-CHROMOSOMES; EXPRESSION ANALYSIS; INHIBITOR POTENCY; SPLICING FACTORS; 68-KDA SUBUNIT; EARLY-STAGE;
D O I
10.1016/j.chom.2018.08.002
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
HIV-1 integration into the host genome favors actively transcribed genes. Prior work indicated that the nuclear periphery provides the architectural basis for integration site selection, with viral capsid-binding host cofactor CPSF6 and viral integrase-binding cofactor LEDGF/p75 contributing to selection of individual sites. Here, by investigating the early phase of infection, we determine that HIV-1 traffics throughout the nucleus for integration. CPSF6-capsid interactions allow the virus to bypass peripheral heterochromatin and penetrate the nuclear structure for integration. Loss of interaction with CPSF6 dramatically alters virus localization toward the nuclear periphery and integration into transcriptionally repressed lamina-associated heterochromatin, while loss of LEDGF/p75 does not significantly affect intranuclear HIV-1 localization. Thus, CPSF6 serves as a master regulator of HIV-1 intranuclear localization by trafficking viral preintegration complexes away from heterochromatin at the periphery toward gene-dense chromosomal regions within the nuclear interior.
引用
收藏
页码:392 / +
页数:21
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