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Journal of Virology, September 2009, p. 9094-9101, Vol. 83, No. 18
0022-538X/09/$08.00+0     doi:10.1128/JVI.02356-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Gag Determinants of Fitness and Drug Susceptibility in Protease Inhibitor-Resistant Human Immunodeficiency Virus Type 1 ^,

Chris M. Parry,^1,2* Arinder Kohli,^1, Christine J. Boinett,¹ Greg J. Towers,¹ Adele L. McCormick,¹ and Deenan Pillay^1,2

UCL/MRC Centre for Medical Molecular Virology, Division of Infection and Immunity, UCL, Windeyer Institute, 46 Cleveland Street, London W1T 4JF, United Kingdom,¹ Virus Reference Department, Centre for Infections, Health Protection Agency, 61 Colindale Avenue, London NW9 2QT, United Kingdom²

Received 12 November 2008/ Accepted 26 June 2009

Mutations can accumulate in the protease and gag genes of human immunodeficiency virus in patients who fail therapy with protease inhibitor drugs. Mutations within protease, the drug target, have been extensively studied. Mutations in gag have been less well studied, mostly concentrating on cleavage sites. A retroviral vector system has been adapted to study full-length gag, protease, and reverse transcriptase genes from patient-derived viruses. Patient plasma-derived mutant full-length gag, protease, and gag-protease from a multidrug-resistant virus were studied. Mutant protease alone led to a 95% drop in replication capacity that was completely rescued by coexpressing the full-length coevolved mutant gag gene. Cleavage site mutations have been shown to improve the replication capacity of mutated protease. Strikingly, in this study, the matrix region and part of the capsid region from the coevolved mutant gag gene were sufficient to achieve full recovery of replication capacity due to the mutant protease, without cleavage site mutations. The same region of gag from a second, unrelated, multidrug-resistant clinical isolate also rescued the replication capacity of the original mutant protease, suggesting a common mechanism that evolves with resistance to protease inhibitors. Mutant gag alone conferred reduced susceptibility to all protease inhibitors and acted synergistically when linked to mutant protease. The matrix region and partial capsid region of gag sufficient to rescue replication capacity also conferred resistance to protease inhibitors. Thus, the amino terminus of Gag has a previously unidentified and important function in protease inhibitor susceptibility and replication capacity.

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* Corresponding author. Mailing address: Virus Reference Department, Centre for Infections, Health Protection Agency, 61 Colindale Avenue, London NW9 5EQ, United Kingdom. Phone: 44 208 327 7812. Fax: 44 208 327 6019. E-mail: chris.parry{at}hpa.org.uk

Published ahead of print on 8 July 2009.

Supplemental material for this article may be found at http://jvi.asm.org/.

Present address: Dental Institute King's College London, St Thomas Street, London SE1 9RT, United Kingdom.

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Journal of Virology, September 2009, p. 9094-9101, Vol. 83, No. 18
0022-538X/09/$08.00+0     doi:10.1128/JVI.02356-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.