西亚试剂：HIV-1 evades innate immune recognition through specific cof

发布时间：2025-05-26

HIV-1 evades innate immune recognition through specific cofactor recruitment

Jane Rasaiyaah，Choon Ping Tan，Adam J. Fletcher，Amanda J. Price，Caroline Blondeau，Laura Hilditch，David A. Jacques，David L. Selwood，Leo C. James，Mahdad Noursadeghi& Greg J. Towers

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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