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Cellular and molecular mechanisms of HIV-1 integration targeting

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Abstract

Integration is central to HIV-1 replication and helps mold the reservoir of cells that persists in AIDS patients. HIV-1 interacts with specific cellular factors to target integration to interior regions of transcriptionally active genes within gene-dense regions of chromatin. The viral capsid interacts with several proteins that are additionally implicated in virus nuclear import, including cleavage and polyadenylation specificity factor 6, to suppress integration into heterochromatin. The viral integrase protein interacts with transcriptional co-activator lens epithelium-derived growth factor p75 to principally position integration within gene bodies. The integrase additionally senses target DNA distortion and nucleotide sequence to help fine-tune the specific phosphodiester bonds that are cleaved at integration sites. Research into virus–host interactions that underlie HIV-1 integration targeting has aided the development of a novel class of integrase inhibitors and may help to improve the safety of viral-based gene therapy vectors.

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Abbreviations

PIC:

Preintegration complex

MoMLV:

Moloney murine leukemia virus

LEDGF:

Lens epithelium-derived growth factor

CPSF6:

Cleavage and polyadenylation specificity factor 6

RNAi:

RNA interference

MLL:

Mixed-lineage leukemia

HDGF:

Hepatoma-derived growth factor

HRP:

HDGF-related protein

HDGFL:

HDGF like

CR:

Charged regions

IBD:

Integrase-binding domain

PHAT:

Pseudo HEAT repeat analogous topology

NTD:

N-terminal domain

CCD:

Catalytic core domain

CTD:

C-terminal domain

PHD:

Plant homeodomain

SMARCB1:

SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily B, member 1

INI1:

Integrase interactor 1

NPC:

Nuclear pore complex

NUP:

Nucleoporin

CYPA:

Cyclophilin A

RNP:

Ribonucleoprotein

RRM:

RNA recognition motif

PRD:

Pro-rich domain

RSLD:

RS-like domain

IN:

Integrase

GFP:

Green fluorescent protein

NLS:

Nuclear localization signal

CFIm:

Cleavage factor I mammalian

ChIP-Seq:

Chromatin-immunoprecipitation sequencing

Y:

Pyrimidine

R:

Purine

LEDGIN:

LEDGF/p75-integrase interaction site

ALLINI:

Allosteric integrase inhibitor

NCINI:

Non-catalytic site integrase inhibitor

INLAI:

Integrase-LEDGF allosteric inhibitor

MDM:

Monocyte-derived macrophages

LRA:

Latency-reversing agent

PDB:

Protein database

TNPO1:

Transportin 1

TNPO3:

Transportin 3

CA:

Capsid

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Acknowledgements

Work in the corresponding author’s laboratory is funded by Grants AI039394 and AI052014 from the US National Institutes of Health. The authors thank Vasudevan Achuthan, Gregory Bedwell, and Sooin Jang for their critical review of the manuscript.

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  1. Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, 450 Brookline Avenue, CLS-1010, Boston, MA, 02215, USA

    Alan N. Engelman & Parmit K. Singh

  2. Department of Medicine, Harvard Medical School, A-111, 25 Shattuck Street, Boston, MA, 02115, USA

    Alan N. Engelman & Parmit K. Singh

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Engelman, A.N., Singh, P.K. Cellular and molecular mechanisms of HIV-1 integration targeting. Cell. Mol. Life Sci. 75, 2491–2507 (2018). https://doi.org/10.1007/s00018-018-2772-5

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