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Nature. 2013 Nov 21;503(7476):402-405. doi: 10.1038/nature12769. Epub 2013 Nov 6.

HIV-1 evades innate immune recognition through specific cofactor recruitment.

Author information

1
University College London, Medical Research Council Centre for Medical Molecular Virology, Division of Infection and Immunity, University College London, 90 Gower St, London WC1E 6BT, United Kingdom.
2
Protein and Nucleic Acid Chemistry Division, Medical Research Council Laboratory of Molecular Biology, Cambridge, UK.
3
Wolfson Institute for Biomedical Research, University College London, Gower Street, London WC1E 6BT, UK.
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Contributed equally

Abstract

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), respectively, 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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PMID:
24196705
PMCID:
PMC3928559
DOI:
10.1038/nature12769
[Indexed for MEDLINE]
Free PMC Article

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