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JAC Advance Access originally published online on February 4, 2008
Journal of Antimicrobial Chemotherapy 2008 61(4):786-791; doi:10.1093/jac/dkm545
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© The Author 2008. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Original research

The HIV-1 protease substitution K55R: a protease-inhibitor-associated substitution involved in restoring viral replication

E. S. Margerison1,*, M. Maguire1, D. Pillay2, P. Cane2 and R. C. Elston1,{dagger}

1 GlaxoSmithKline, Gunnels Wood Road, Stevenage SG1 2NY, UK 2 Centre for Infections, Health Protection Agency, 61 Colindale Avenue, London NW9 5HT, UK

Received 17 September 2007; returned 4 November 2007; revised 17 December 2007; accepted 18 December 2007

* Correspondence address. Lab21 Ltd, 184 Cambridge Science Park, Milton Road, Cambridge CB4 0GA, UK. Tel: +44-1223-395484; Fax: +44-1223-395491; E-mail: liz.margerison{at}lab-21.com

Objectives: The identification and in vitro characterization of novel protease mutations strongly associated with known protease resistance mutations.

Methods: The association between pairs of protease amino acid substitutions was identified using a database of protease sequences derived from protease inhibitor-experienced patients (n = 803). In vitro characterization included drug susceptibility and viral replication studies performed on recombinant viruses harbouring site-directed mutations.

Results: The K55R mutation, which is not a natural polymorphism, was identified to be strongly associated with protease mutations M46I/L and to a lesser extent L24I, I54V and V82A/T/S/F. In vitro characterization of the K55R substitution indicated a primary role for this substitution in increasing replicative capacity in the presence of specific protease mutations.

Conclusions: The K55R mutation is a secondary drug resistance mutation that can improve viral replication capacity in the presence of other primary protease mutations.

Keywords: HIV , fitness , resistance , mutations

{dagger} Present address. Roche Products Limited, Hexagon Place, Shire Park, Welwyn Garden City AL7 1TW, UK.


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