Schaller, T;
Ocwieja, KE;
Rasaiyaah, J;
Price, AJ;
Brady, TL;
Roth, SL;
Hué, S;
... Towers, GJ; + view all
(2011)
HIV-1 capsid-cyclophilin interactions determine nuclear import pathway, integration targeting and replication efficiency.
PLoS Pathog
, 7
(12)
, Article e1002439. 10.1371/journal.ppat.1002439.
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Abstract
Lentiviruses such as HIV-1 traverse nuclear pore complexes (NPC) and infect terminally differentiated non-dividing cells, but how they do this is unclear. The cytoplasmic NPC protein Nup358/RanBP2 was identified as an HIV-1 co-factor in previous studies. Here we report that HIV-1 capsid (CA) binds directly to the cyclophilin domain of Nup358/RanBP2. Fusion of the Nup358/RanBP2 cyclophilin (Cyp) domain to the tripartite motif of TRIM5 created a novel inhibitor of HIV-1 replication, consistent with an interaction in vivo. In contrast to CypA binding to HIV-1 CA, Nup358 binding is insensitive to inhibition with cyclosporine, allowing contributions from CypA and Nup358 to be distinguished. Inhibition of CypA reduced dependence on Nup358 and the nuclear basket protein Nup153, suggesting that CypA regulates the choice of the nuclear import machinery that is engaged by the virus. HIV-1 cyclophilin-binding mutants CA G89V and P90A favored integration in genomic regions with a higher density of transcription units and associated features than wild type virus. Integration preference of wild type virus in the presence of cyclosporine was similarly altered to regions of higher transcription density. In contrast, HIV-1 CA alterations in another patch on the capsid surface that render the virus less sensitive to Nup358 or TRN-SR2 depletion (CA N74D, N57A) resulted in integration in genomic regions sparse in transcription units. Both groups of CA mutants are impaired in replication in HeLa cells and human monocyte derived macrophages. Our findings link HIV-1 engagement of cyclophilins with both integration targeting and replication efficiency and provide insight into the conservation of viral cyclophilin recruitment.
| Type: | Article |
|---|---|
| Title: | HIV-1 capsid-cyclophilin interactions determine nuclear import pathway, integration targeting and replication efficiency. |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1371/journal.ppat.1002439 |
| Publisher version: | http://dx.doi.org/10.1371/journal.ppat.1002439 |
| Language: | English |
| Additional information: | This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. Funding: This work was funded by Wellcome Trust fellowship (WT090940) to GJT and grants from the National Institute of Health Research UCL/UCLH Comprehensive Biomedical Research Centre and the Medical Research Council (GJT) and NIH grants AI52845 and AI082020, the University of Pennsylvania Center for AIDS Research, and the Penn Genome Frontiers Institute via a grant with the Pennsylvania Department of Health (FDB). The United States Department of Health specifically disclaims responsibility for any analyses, interpretations, or conclusions. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. |
| Keywords: | Active Transport, Cell Nucleus, Blotting, Western, Capsid Proteins, Cell Line, Cell Nucleus, Cyclophilin A, HIV Infections, HIV-1, HeLa Cells, Humans, Macrophages, Molecular Chaperones, Nuclear Pore Complex Proteins, Reverse Transcriptase Polymerase Chain Reaction, Virus Replication |
| 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 > Cancer Institute UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Cancer Bio UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Infection, Immunity and Inflammation Dept |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/1333940 |
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