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Journal of Virology, September 2008, p. 9228-9235, Vol. 82, No. 18
0022-538X/08/$08.00+0     doi:10.1128/JVI.01535-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Analysis of Natural Sequence Variation and Covariation in Human Immunodeficiency Virus Type 1 Integrase {triangledown}

Richard E. Myers1* and Deenan Pillay1,2

Virus Reference Department, Centre for Infections, Health Protection Agency, London, United Kingdom,1 Centre for Virology, Division of Infection and Immunity, University College London, United Kingdom2

Received 13 July 2007/ Accepted 25 June 2008

Human immunodeficiency virus type 1 (HIV-1) integrase inhibitors are in clinical trials, and raltegravir and elvitegravir are likely to be the first licensed drugs of this novel class of HIV antivirals. Understanding resistance to these inhibitors is important to maximize their efficacy. It has been shown that natural variation and covariation provide valuable insights into the development of resistance for established HIV inhibitors. Therefore, we have undertaken a study to fully characterize natural polymorphisms and amino acid covariation within an inhibitor-naïve sequence set spanning all defined HIV-1 subtypes. Inter- and intrasubtype variation was greatest in a 50-amino-acid segment of HIV-1 integrase incorporating the catalytic aspartic acid codon 116, suggesting that polymorphisms affect inhibitor binding and pathways to resistance. The critical mutations that determine the resistance pathways to raltegravir and elvitegravir (N155H, Q148K/R/H, and E92Q) were either rare or absent from the 1,165-sequence data set. However, 25 out of 41 mutations associated with integrase inhibitor resistance were present. These mutations were not subtype associated and were more prevalent in the subtypes that had been sampled frequently within the database. A novel modification of the Jaccard index was used to analyze amino acid covariation within HIV-1 integrase. A network of 10 covarying resistance-associated mutations was elucidated, along with a further 15 previously undescribed mutations that covaried with at least two of the resistance positions. The validation of covariation as a predictive tool will be dependent on monitoring the evolution of HIV-1 integrase under drug selection pressure.

* Corresponding author. Mailing address: Virus Reference Department, Centre for Infections, Health Protection Agency, 61 Colindale Avenue, London NW9 5EQ, United Kingdom. Phone: 2083276071. Fax: 2082001569. E-mail: Richard.Myers{at}hpa.org.uk

{triangledown} Published ahead of print on 2 July 2008.

Journal of Virology, September 2008, p. 9228-9235, Vol. 82, No. 18
0022-538X/08/$08.00+0     doi:10.1128/JVI.01535-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Low, A., Prada, N., Topper, M., Vaida, F., Castor, D., Mohri, H., Hazuda, D., Muesing, M., Markowitz, M. (2009). Natural Polymorphisms of Human Immunodeficiency Virus Type 1 Integrase and Inherent Susceptibilities to a Panel of Integrase Inhibitors. Antimicrob. Agents Chemother. 53: 4275-4282 [Abstract] [Full Text]  
  • da Silva, J. (2009). Amino Acid Covariation in a Functionally Important Human Immunodeficiency Virus Type 1 Protein Region Is Associated With Population Subdivision. Genetics 182: 265-275 [Abstract] [Full Text]  


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