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Cell Host Microbe. 2018 Sep 12;24(3):392-404.e8. doi: 10.1016/j.chom.2018.08.002. Epub 2018 Aug 30.

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

Author information

1
Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
2
Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA 01655, USA.
3
Department of Molecular Microbiology & Immunology, University of Missouri School of Medicine, Columbia, MO 65212, USA.
4
Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
5
Leidos Biomedical Research, Inc., Frederick, MD 21702, USA.
6
Division of Molecular Medicine, Mayo Clinic, Rochester, MN 55905, USA.
7
Division of Infectious Diseases, University of Colorado Denver School of Medicine, Aurora, CO 80045, USA.
8
HIV Dynamics and Replication Program, National Cancer Institute, Frederick, MD 21702, USA.
9
Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA 01655, USA; Gastroenterology Division, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA. Electronic address: abraham.brass@umassmed.edu.
10
Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. Electronic address: alan_engelman@dfci.harvard.edu.

Abstract

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.

KEYWORDS:

CPSF6; HIV capsid; HIV integrase; HIV integration; HIV trafficking; LEDGF/p75; lamina-associated domain; nuclear trafficking

PMID:
30173955
PMCID:
PMC6368089
DOI:
10.1016/j.chom.2018.08.002
[Indexed for MEDLINE]
Free PMC Article

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