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    Publication Date: 2013-11-08
    Description: 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-kappaB 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.〈br /〉〈br /〉〈a href="" target="_blank"〉〈img src="" border="0"〉〈/a〉   〈a href="" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Rasaiyaah, Jane -- Tan, Choon Ping -- Fletcher, Adam J -- Price, Amanda J -- Blondeau, Caroline -- Hilditch, Laura -- Jacques, David A -- Selwood, David L -- James, Leo C -- Noursadeghi, Mahdad -- Towers, Greg J -- 090940/Wellcome Trust/United Kingdom -- G0501446/Medical Research Council/United Kingdom -- G0900950/Medical Research Council/United Kingdom -- G9721629/Medical Research Council/United Kingdom -- MC_PC_12024/Medical Research Council/United Kingdom -- MC_U105181010/Medical Research Council/United Kingdom -- Medical Research Council/United Kingdom -- England -- Nature. 2013 Nov 21;503(7476):402-5. doi: 10.1038/nature12769. Epub 2013 Nov 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉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.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="" target="_blank"〉PubMed〈/a〉
    Keywords: Capsid Proteins/genetics/metabolism ; Cyclophilins/metabolism ; Cyclosporine/metabolism ; HIV Infections/immunology/metabolism/pathology/virology ; HIV-1/*immunology/metabolism ; Humans ; *Immune Evasion ; Immunity, Innate/*immunology ; Interferon Regulatory Factor-3/metabolism ; Interferon Type I/immunology/secretion ; Macrophages/cytology/*immunology/pathology/*virology ; Molecular Chaperones/metabolism ; Monocytes/cytology ; NF-kappa B/metabolism ; Nuclear Pore Complex Proteins/metabolism ; Receptors, Pattern Recognition ; Virus Internalization ; Virus Replication/immunology ; mRNA Cleavage and Polyadenylation Factors/deficiency/genetics/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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