Article abstract
Nature Structural & Molecular Biology 16, 1036 - 1042 (2009)
Published online: 20 September 2009 | doi:10.1038/nsmb.1667
Active site remodeling switches HIV specificity of antiretroviral TRIMCyp
Amanda J Price1,4, Flavia Marzetta2,3,4, Michael Lammers1, Laura M J Ylinen2, Torsten Schaller2, Sam J Wilson2,3, Greg J Towers2 & Leo C James1
Abstract
TRIMCyps are primate antiretroviral proteins that potently inhibit HIV replication. Here we describe how rhesus macaque TRIMCyp (RhTC) has evolved to target and restrict HIV-2. We show that the ancestral cyclophilin A (CypA) domain of RhTC targets HIV-2 capsid with weak affinity, which is strongly increased in RhTC by two mutations (D66N and R69H) at the expense of HIV-1 binding. These mutations disrupt a constraining intramolecular interaction in CypA, triggering the complete restructuring (>16 Å) of an active site loop. This new configuration discriminates between divergent HIV-1 and HIV-2 loop conformations mediated by capsid residue 88. Viral sensitivity to RhTC restriction can be conferred or abolished by mutating position 88. Furthermore, position 88 determines the susceptibility of naturally occurring HIV-1 sequences to restriction. Our results reveal the complex molecular, structural and thermodynamic changes that underlie the ongoing evolutionary race between virus and host.
- Protein and Nucleic Acid Chemistry Division, Medical Research Council Laboratory of Molecular Biology, Cambridge, UK.
- Division of Infection and Immunity, Medical Research Council Centre for Medical Molecular Virology, University College London, London, UK.
- Present addresses: Viral Pathogens and Biosafety Unit, Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Milano, Italy (F.M.); Aaron Diamond AIDS Research Center, Howard Hughes Medical Institute and the Rockefeller University, New York, New York, USA.
- These authors contributed equally to this work.
Correspondence to: Greg J Towers2 e-mail: g.towers@ucl.ac.uk
Correspondence to: Leo C James1 e-mail: lcj@mrc-lmb.cam.ac.uk.
MORE ARTICLES LIKE THIS
These links to content published by NPG are automatically generated.
NEWS AND VIEWS
Research HighlightsNature Immunology News and Views (01 Aug 2004)
HIV-1 infection: fooling the gatekeeperNature Medicine News and Views (01 Sep 2003)
See all 3 matches for News And ViewsRESEARCH
Tissue-specific restriction of cyclophilin A-independent HIV-1- and SIV-derived lentiviral vectorsGene Therapy Original Article
Cyclophilin A modulates the sensitivity of HIV-1 to host restriction factorsNature Medicine Article (01 Sep 2003)
See all 17 matches for Research
