title: HIV-1 evades innate immune recognition through specific cofactor recruitment.
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.
authors.affiliation: 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.
authors.forename: Jane
authors.initials: J
authors.lastname: Rasaiyaah
authors.affiliation: 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.
authors.forename: Choon Ping
authors.initials: CP
authors.lastname: Tan
authors.affiliation: 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.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Fletcher
authors.affiliation: Protein and Nucleic Acid Chemistry Division, Medical Research Council Laboratory of Molecular Biology, Cambridge, UK.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Price
authors.affiliation: 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.
authors.forename: Caroline
authors.initials: C
authors.lastname: Blondeau
authors.affiliation: 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.
authors.forename: Laura
authors.initials: L
authors.lastname: Hilditch
authors.affiliation: Protein and Nucleic Acid Chemistry Division, Medical Research Council Laboratory of Molecular Biology, Cambridge, UK.
authors.forename: David A
authors.initials: DA
authors.lastname: Jacques
authors.affiliation: Wolfson Institute for Biomedical Research, University College London, Gower Street, London WC1E 6BT, UK.
authors.forename: David L
authors.initials: DL
authors.lastname: Selwood
authors.affiliation: Protein and Nucleic Acid Chemistry Division, Medical Research Council Laboratory of Molecular Biology, Cambridge, UK.
authors.forename: Leo C
authors.initials: LC
authors.lastname: James
authors.affiliation: 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.
authors.forename: Mahdad
authors.initials: M
authors.lastname: Noursadeghi
authors.affiliation: 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.
authors.forename: Greg J
authors.initials: GJ
authors.lastname: Towers
mesh_terms: D036022:Capsid Proteins / Q000235:genetics / Q000378:metabolism; D021983:Cyclophilins / Q000378:metabolism; D016572:Cyclosporine / Q000378:metabolism; D015658:HIV Infections / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000821:virology; D015497:HIV-1 / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D057131:Immune Evasion; D007113:Immunity, Innate / Q000276:immunology*; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D007370:Interferon Type I / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000276:immunology* / Q000473:pathology / Q000821:virology*; D018832:Molecular Chaperones / Q000378:metabolism; D009000:Monocytes / Q000166:cytology; D016328:NF-kappa B / Q000378:metabolism; D028861:Nuclear Pore Complex Proteins / Q000378:metabolism; D051192:Receptors, Pattern Recognition; D053586:Virus Internalization; D014779:Virus Replication / Q000276:immunology; D039221:mRNA Cleavage and Polyadenylation Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism
chemical_list: D036022:Capsid Proteins; C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I; D018832:Molecular Chaperones; D016328:NF-kappa B; D028861:Nuclear Pore Complex Proteins; D051192:Receptors, Pattern Recognition; C450562:cleavage factor Im, human; D039221:mRNA Cleavage and Polyadenylation Factors; C094493:ran-binding protein 2; D016572:Cyclosporine; D021983:Cyclophilins