4IPZ

SmBz bound to Cyclophilin A

Summary for 4IPZ

• Entry DOI: 10.2210/pdb4ipz/pdb
• Related PRD ID: PRD_001130
• Descriptor: Peptidyl-prolyl cis-trans isomerase A, cyclosporine SmBz-CsA, CHLORIDE ION, ... (4 entities in total)
• Functional Keywords: cyclophilin fold, peptidyl-prolyl isomerase, cyclosporine a, isomerase-isomerase inhibitor complex, isomerase/isomerase inhibitor
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 19462.17

Authors

Price, A.J.,Jacques, D.A.,James, L.C. (deposition date: 2013-01-10, release date: 2013-11-06, Last modification date: 2024-05-08)

Primary citation

Rasaiyaah, J.,Tan, C.P.,Fletcher, A.J.,Price, A.J.,Blondeau, C.,Hilditch, L.,Jacques, D.A.,Selwood, D.L.,James, L.C.,Noursadeghi, M.,Towers, G.J.
HIV-1 evades innate immune recognition through specific cofactor recruitment.
Nature, 503:402-405, 2013

PubMed 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.

PubMed: 24196705
DOI: 10.1038/nature12769

Experimental method

X-RAY DIFFRACTION (1.67 Å)