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Conformational Adaptation of Asian Macaque TRIMCyp Directs Lineage Specific Antiviral Activity

Ylinen, LMJ; Price, AJ; Rasaiyaah, J; Hue, S; Rose, NJ; Marzetta, F; James, LC; (2010) Conformational Adaptation of Asian Macaque TRIMCyp Directs Lineage Specific Antiviral Activity. PLOS PATHOG , 6 (8) , Article e1001062. 10.1371/journal.ppat.1001062. Green open access

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Abstract

TRIMCyps are anti-retroviral proteins that have arisen independently in New World and Old World primates. All TRIMCyps comprise a CypA domain fused to the tripartite domains of TRIM5 alpha but they have distinct lentiviral specificities, conferring HIV-1 restriction in New World owl monkeys and HIV-2 restriction in Old World rhesus macaques. Here we provide evidence that Asian macaque TRIMCyps have acquired changes that switch restriction specificity between different lentiviral lineages, resulting in species-specific alleles that target different viruses. Structural, thermodynamic and viral restriction analysis suggests that a single mutation in the Cyp domain, R69H, occurred early in macaque TRIMCyp evolution, expanding restriction specificity to the lentiviral lineages found in African green monkeys, sooty mangabeys and chimpanzees. Subsequent mutations have enhanced restriction to particular viruses but at the cost of broad specificity. We reveal how specificity is altered by a scaffold mutation, E143K, that modifies surface electrostatics and propagates conformational changes into the active site. Our results suggest that lentiviruses may have been important pathogens in Asian macaques despite the fact that there are no reported lentiviral infections in current macaque populations.

Type: Article
Title: Conformational Adaptation of Asian Macaque TRIMCyp Directs Lineage Specific Antiviral Activity
Open access status: An open access version is available from UCL Discovery
DOI: 10.1371/journal.ppat.1001062
Publisher version: http://dx.doi.org/10.1371/journal.ppat.1001062
Language: English
Additional information: © 2010 Ylinen et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was funded by a Wellcome Trust senior fellowship (WT076608) to GJT, the Medical Research Council, the Department of Health, the National Institute for Health Research UCLH/UCL Comprehensive Biomedical Research Centre and the European Community's Seventh Framework Programme (FP7/2007-2013) under the project Collaborative HIV and Anti-HIV Drug Resistance Network (CHAIN) grant agreement 223131. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Keywords: IMMUNODEFICIENCY-VIRUS TYPE-2, CYCLOPHILIN-A, RETROVIRAL RESTRICTION, TRIM5-ALPHA RESTRICTION, REVERSE TRANSCRIPTION, ENDOGENOUS LENTIVIRUS, HIV-1 INFECTION, WORLD PRIMATES, SPRY DOMAIN, IN-VIVO
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > UCL GOS Institute of Child Health > ICH Infect, Imm, Infla. and Physio Med
URI: https://discovery.ucl.ac.uk/id/eprint/144208
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