Conformational Adaptation of Asian Macaque TRIMCyp Directs Lineage Specific Antiviral Activity

PLoS Pathogens

Amanda J. Price¹  Nicola J. Rose¹  Leo C. James¹  Jane Rasaiyaah²  Greg J. Towers³  Stéphane Hué⁴  Flavia Marzetta⁴  Laura M. J. Ylinen⁴ 

[1] Division of Infection and Immunity, University College London, London, United Kingdom;Medical Research Council Laboratory of Molecular Biology, Protein and Nucleic Acid Chemistry Division, Cambridge, United Kingdom;The National Institute for Biological Standards and Control, A Centre of the Health Protection Agency, Potters Bar, Hertfordshire, United Kingdom;University College London Medical Research Council Centre for Medical Molecular Virology, London, United Kingdom

关键词: Macaque;    HIV-1;    HIV-2;    Capsids;    FIV;    Viral evolution;    Vector-borne diseases;    Primates;   

DOI  :  10.1371/journal.ppat.1001062

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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 TRIM5α 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.

【 授权许可】

CC BY