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HIV Integration Targeting: A Pathway Involving Transportin-3 and the Nuclear Pore Protein RanBP2

Ocwieja, KE; Brady, TL; Ronen, K; Huegel, A; Roth, SL; Schaller, T; James, LC; ... Bushman, FD; + view all (2011) HIV Integration Targeting: A Pathway Involving Transportin-3 and the Nuclear Pore Protein RanBP2. PLOS PATHOG , 7 (3) , Article e1001313. 10.1371/journal.ppat.1001313. Green open access

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Abstract

Genome-wide siRNA screens have identified host cell factors important for efficient HIV infection, among which are nuclear pore proteins such as RanBP2/Nup358 and the karyopherin Transportin-3/TNPO3. Analysis of the roles of these proteins in the HIV replication cycle suggested that correct trafficking through the pore may facilitate the subsequent integration step. Here we present data for coupling between these steps by demonstrating that depletion of Transportin-3 or RanBP2 altered the terminal step in early HIV replication, the selection of chromosomal sites for integration. We found that depletion of Transportin-3 and RanBP2 altered integration targeting for HIV. These knockdowns reduced HIV integration frequency in gene-dense regions and near gene-associated features, a pattern that differed from that reported for depletion of the HIV integrase binding cofactor Psip1/Ledgf/p75. MLV integration was not affected by the Transportin-3 knockdown. Using siRNA knockdowns and integration targeting analysis, we also implicated several additional nuclear proteins in proper target site selection. To map viral determinants of integration targeting, we analyzed a chimeric HIV derivative containing MLV gag, and found that the gag replacement phenocopied the Transportin-3 and RanBP2 knockdowns. Thus, our data support a model in which Gag-dependent engagement of the proper transport and nuclear pore machinery mediate trafficking of HIV complexes to sites of integration.

Type: Article
Title: HIV Integration Targeting: A Pathway Involving Transportin-3 and the Nuclear Pore Protein RanBP2
Open access status: An open access version is available from UCL Discovery
DOI: 10.1371/journal.ppat.1001313
Publisher version: http://dx.doi.org/10.1371/journal.ppat.1001313
Language: English
Additional information: © 2011 Ocwieja et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by NIH grants AI52845 and AI082020, the University of Pennsylvania Center for AIDS Research, and the Penn Genome Frontiers Institute with a grant with the Pennsylvania Department of Health. The Department of Health specifically disclaims responsibility for any analyses, interpretations, or conclusions. GJT is supported by Wellcome Trust Senior Fellowship no. WT076608, the UCL/UCLH National Institute of Health Research Comprehensive Biomedical Research Centre and the Medical Research Council. KEO was supported by NIH training grant T32 AI007324. TLB is a Special Fellow of the Leukemia and Lymphoma Society of America. KR was supported by NIH training grant T32 AI-07324-17. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Keywords: HUMAN-IMMUNODEFICIENCY-VIRUS, SITE SELECTION, NONDIVIDING CELLS, HUMAN GENOME, PREINTEGRATION COMPLEXES, RETROVIRAL INTEGRATION, DNA INTEGRATION, ACTIVE GENES, TYPE-1 CDNA, LEDGF/P75
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity
URI: https://discovery.ucl.ac.uk/id/eprint/1304455
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