[en] 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.
Disciplines :
Life sciences: Multidisciplinary, general & others
Author, co-author :
Rasaiyaah, Jane; University College London - UCL > Infection and Immunity > Medical Research Council Centre for Medical Molecular Virology
Ping Tan, Choon; University College London - UCL > Infection and Immunity > Medical Research Council Centre for Medical Molecular Virology
Fletcher, Adam; University College London - UCL > Infection and Immunity > Medical Research Council Centre for Medical Molecular Virology
Price, Amanda; Medical Research Council Laboratory of Molecular Biology, Cambridge, UK > Protein and Nucleic Acid Chemistry Division
Blondeau, Caroline ; University College London - UCL > Infection and Immunity > Medical Research Council Centre for Medical Molecular Virology
Hilditch, Laura; University College London - UCL > Infection and Immunity > Medical Research Council Centre for Medical Molecular Virology
Jacques, David; Medical Research Council Laboratory of Molecular Biology, Cambridge, UK > Protein and Nucleic Acid Chemistry Division
Selwood, David; University College London - UCL > Wolfson Institute for Biomedical Research
James, Leo; Medical Research Council Laboratory of Molecular Biology, Cambridge, UK > Protein and Nucleic Acid Chemistry Division
Noursadeghi, Mahdad; University College London - UCL > Infection and Immunity > Medical Research Council Centre for Medical Molecular Virology
Towers, Greg; University College London - UCL > Infection and Immunity > Medical Research Council Centre for Medical Molecular Virology
Language :
English
Title :
HIV-1 evades innate immune recognition through specific cofactor recruitment
Publication date :
2013
Journal title :
Nature
ISSN :
0028-0836
eISSN :
1476-4687
Publisher :
Nature Publishing Group, Basingstoke, United Kingdom
scite shows how a scientific paper has been cited by providing the context of the citation, a classification describing whether it supports, mentions, or contrasts the cited claim, and a label indicating in which section the citation was made.
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