HIV-1 Capsid-Cyclophilin Interactions Determine Nuclear Import Pathway, Integration Targeting and Replication Efficiency

PLoS Pathogens

Vineet N. KewalRamani¹  KyeongEun Lee¹  Amanda J. Price²  Leo C. James²  Jane Rasaiyaah³  Greg J. Towers³  Richard G. Jenner³  Adam J. Fletcher³  Torsten Schaller³  Mahdad Noursadeghi³  Stéphane Hué³  Shoshannah L. Roth⁴  Frederic D. Bushman⁴  Karen E. Ocwieja⁴  Troy L. Brady⁴ 

[1] HIV Drug Resistance Program, National Cancer Institute, Frederick, Maryland, United States of America;Medical Research Council Laboratory of Molecular Biology, Protein and Nucleic Acid Chemistry Division, Cambridge, United Kingdom;University College London Medical Research Council Centre for Medical Molecular Virology, Division of Infection and Immunity, London, United Kingdom;University of Pennsylvania School of Medicine, Department of Microbiology, Philadelphia, Pennsylvania, United States of America

关键词: HIV-1;    Infectious disease control;    Viral replication;    Vector-borne diseases;    RNA interference;    HeLa cells;    DNA transcription;    Viral packaging;   

DOI  :  10.1371/journal.ppat.1002439

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

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