Letter | Published:

HIV-1 evades innate immune recognition through specific cofactor recruitment

Nature volume 503, pages 402405 (21 November 2013) | Download Citation


This article has been updated


Human immunodeficiency virus (HIV)-1 is able to replicate in primary human macrophages without stimulating innate immunity despite reverse transcription of genomic RNA into double-stranded DNA, an activity that might be expected to trigger innate pattern recognition receptors. We reasoned that if correctly orchestrated HIV-1 uncoating and nuclear entry is important for evasion of innate sensors then manipulation of specific interactions between HIV-1 capsid and host factors that putatively regulate these processes should trigger pattern recognition receptors and stimulate type 1 interferon (IFN) secretion. Here we show that HIV-1 capsid mutants N74D and P90A, which are impaired for interaction with cofactors cleavage and polyadenylation specificity factor subunit 6 (CPSF6) and cyclophilins (Nup358 and CypA), respectively1,2, cannot replicate in primary human monocyte-derived macrophages because they trigger innate sensors leading to nuclear translocation of NF-κB and IRF3, the production of soluble type 1 IFN and induction of an antiviral state. Depletion of CPSF6 with short hairpin RNA expression allows wild-type virus to trigger innate sensors and IFN production. In each case, suppressed replication is rescued by IFN-receptor blockade, demonstrating a role for IFN in restriction. IFN production is dependent on viral reverse transcription but not integration, indicating that a viral reverse transcription product comprises the HIV-1 pathogen-associated molecular pattern. Finally, we show that we can pharmacologically induce wild-type HIV-1 infection to stimulate IFN secretion and an antiviral state using a non-immunosuppressive cyclosporine analogue. We conclude that HIV-1 has evolved to use CPSF6 and cyclophilins to cloak its replication, allowing evasion of innate immune sensors and induction of a cell-autonomous innate immune response in primary human macrophages.

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Change history

  • 20 November 2013

    Figure 3 was corrected and changes were made to the Acknowledgements section.



Protein Data Bank

Data deposits

Structural coordinates have been deposited under PDB accession code 4IPZ. Microarray data are available from the EBI Array Express repository under accession no. E-MTAB-1437.


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We are grateful to J. W. Chin, S. Goodbourn, K. Lee, O. Perisic and V. KewalRamani for reagents and advice. This work was funded by Wellcome Trust Senior Fellowship 090940 to G.J.T., the Medical Research Council, an MRC Confidence in Concept Award to G.J.T. and D.S. and the National Institute for Health Research (NIHR) University College London Hospitals Biomedical Research Centre. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.

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Author notes

    • Mahdad Noursadeghi
    •  & Greg J. Towers

    These authors contributed equally to this work.


  1. University College London, Medical Research Council Centre for Medical Molecular Virology, Division of Infection and Immunity, University College London, 90 Gower Street, London WC1E 6BT, UK

    • Jane Rasaiyaah
    • , Choon Ping Tan
    • , Adam J. Fletcher
    • , Caroline Blondeau
    • , Laura Hilditch
    • , Mahdad Noursadeghi
    •  & Greg J. Towers
  2. Protein and Nucleic Acid Chemistry Division, Medical Research Council Laboratory of Molecular Biology, Cambridge CB2 0QH, UK

    • Amanda J. Price
    • , David A. Jacques
    •  & Leo C. James
  3. Wolfson Institute for Biomedical Research, University College London, Gower Street, London WC1E 6BT, UK

    • David L. Selwood


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J.R., C.P.T., A.J.F., D.L.S., M.N. and G.J.T. designed the study. J.R. performed all experiments in MDM, C.P.T. performed cGAMP and immunostimulatory RNA assays, A.J.F. performed CPSF6 experiments in HeLa cells. A.J.P. solved the structure of SmBz-CsC in complex with CypA and L.H. performed the TRIMCyp experiments. J.R., A.J.F., A.J.P., L.H., D.A.J., L.C.J., M.N. and G.J.T. analysed the data. A.J.F. and C.B. generated constructs and D.L.S. synthesized SmBz-CsA. J.R., M.N. and G.J.T. wrote the manuscript.

Competing interests

J.R., L.C.J., D.S. and G.J.T. are inventors on a patent claiming the anti-HIV activity of SmBz-CsA.

Corresponding authors

Correspondence to Mahdad Noursadeghi or Greg J. Towers.

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