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Journal of Virology, March 2009, p. 2645-2654, Vol. 83, No. 6
0022-538X/09/$08.00+0     doi:10.1128/JVI.01556-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Demonstration of Sustained Drug-Resistant Human Immunodeficiency Virus Type 1 Lineages Circulating among Treatment-Naïve Individuals{triangledown} ,{dagger}

Stéphane Hué,1* Robert J. Gifford,2 David Dunn,3 Esther Fernhill,3 Deenan Pillay,1,4 on Behalf of the UK Collaborative Group on HIV Drug Resistance

UCL/MRC Centre for Medical Molecular Virology, University College London, Windeyer Building, 46 Cleveland Street, London W1T 4JF, United Kingdom,1 Division of Infection Diseases, Stanford University, Stanford, California 94305,2 Medical Research Centre Clinical Trials Unit, London NW1 2DA, United Kingdom,3 Centre for Infections, Health Protection Agency, 61 Colindale Avenue, London NW9 5EQ, United Kingdom4

Received 23 July 2008/ Accepted 24 December 2008

Transmission of human immunodeficiency virus (HIV) drug resistance is well-recognized and compromises response to first-line therapy. However, the population dynamics of transmitted resistance remains unclear, although previous models have assumed that such transmission reflects direct infection from treated individuals. We investigated whether population-based phylogenetic analyses would uncover lineages of resistant viruses circulating in untreated individuals. Through the phylogenetic analysis of 14,061 HIV type 1 (HIV-1) pol gene sequences generated in the United Kingdom from both treatment-naïve and -experienced individuals, we identified five treatment-independent viral clusters containing mutations conferring cross-resistance to antiretroviral drugs prescribed today in the United Kingdom. These viral lineages represent sustainable reservoirs of resistance among new HIV infections, independent of treatment. Dated phylogenies reconstructed through Bayesian Markov chain Monte Carlo inference indicated that these reservoirs originated between 1997 and 2003 and have persisted in the HIV-infected population for up to 8 years. Since our cohort does not represent all infected individuals within the United Kingdom, our results are likely to underestimate the number and size of the resistant reservoirs circulating among drug-naïve patients. The existence of sustained reservoirs of resistance in the absence of treatment has the capacity to threaten the long-term efficacy of antiretroviral therapy and suggests there is a limit to the decline of transmitted drug resistance. Given the current decrease in resistance transmitted from treated individuals, a greater proportion of resistance is likely to come from drug-naïve lineages. These findings provide new insights for the planning and management of treatment programs in resource-rich and developing countries.

* Corresponding author. Mailing address: Centre for Virology, University College London, Windeyer Building, 46 Cleveland Street, London W1T 4JF, United Kingdom. Phone: 44 20 7679 9226. Fax: 44 20 7580 5896. E-mail: stephane.hue{at}ucl.ac.uk

{triangledown} Published ahead of print on 21 January 2009.

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

Journal of Virology, March 2009, p. 2645-2654, Vol. 83, No. 6
0022-538X/09/$08.00+0     doi:10.1128/JVI.01556-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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