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Open Access Research article

Superinfection with drug-resistant HIV is rare and does not contribute substantially to therapy failure in a large European cohort

István Bartha1234, Matthias Assel5, Peter MA Sloot6, Maurizio Zazzi7, Carlo Torti89, Eugen Schülter10, Andrea De Luca1112, Anders Sönnerborg13, Ana B Abecasis14, Kristel Van Laethem15, Andrea Rosi7, Jenny Svärd13, Roger Paredes16, David AMC van de Vijver17, Anne-Mieke Vandamme1415 and Viktor Müller118*

Author Affiliations

1 Institute of Biology, Eötvös Loránd University, Budapest, Hungary

2 School of Life Sciences, École Polytechnique Fédérale De Lausanne, Lausanne, Switzerland

3 Institute of Microbiology, University Hospital and University of Lausanne, Lausanne, Switzerland

4 Swiss Institute of Bioinformatics, Lausanne, Switzerland

5 High Performance Computing Centre, University of Stuttgart, Stuttgart, Germany

6 Computational Science, The University of Amsterdam, Amsterdam, The Netherlands

7 Department of Medical Biotechnologies, University of Siena, Siena, Italy

8 Institute of Infectious and Tropical Diseases, University of Brescia, Brescia, Italy

9 Unit of Infectious Diseases, Department of Medical and Surgical Sciences, University “Magna Graecia”, Catanzaro, Italy

10 Institute of Virology, University of Cologne, Cologne, Germany

11 Institute of Clinical infectious Diseases, Università Cattolica del Sacro Cuore, Roma, Italy

12 University Division of Infectious Diseases, Siena University Hospital, Siena, Italy

13 Department of Infectious Diseases, Karolinska Institute, Stockholm, Sweden

14 Centro de Malária e Outras Doenças Tropicais, Unidade de Microbiologia e Unidade de Saúde Pública e Internacional; Instituto de Higiene e Medicina Tropical, Lisboa, Portugal

15 Rega Institute for Medical Research, Department of Microbiology and Immunology, KU Leuven, Leuven, Belgium

16 Fundacions IrsiCaixa I Lluita contra la SIDA, Universitat Autònoma de Barcelona, Badalona, Spain

17 Erasmus Medical Centre, Erasmus University Rotterdam, Viroscience, Rotterdam, The Netherlands

18 Research Group of Theoretical Biology and Evolutionary Ecology, Eötvös Loránd University and the Hungarian Academy of Sciences, Budapest, Hungary

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BMC Infectious Diseases 2013, 13:537  doi:10.1186/1471-2334-13-537

Published: 12 November 2013

Abstract

Background

Superinfection with drug resistant HIV strains could potentially contribute to compromised therapy in patients initially infected with drug-sensitive virus and receiving antiretroviral therapy. To investigate the importance of this potential route to drug resistance, we developed a bioinformatics pipeline to detect superinfection from routinely collected genotyping data, and assessed whether superinfection contributed to increased drug resistance in a large European cohort of viremic, drug treated patients.

Methods

We used sequence data from routine genotypic tests spanning the protease and partial reverse transcriptase regions in the Virolab and EuResist databases that collated data from five European countries. Superinfection was indicated when sequences of a patient failed to cluster together in phylogenetic trees constructed with selected sets of control sequences. A subset of the indicated cases was validated by re-sequencing pol and env regions from the original samples.

Results

4425 patients had at least two sequences in the database, with a total of 13816 distinct sequence entries (of which 86% belonged to subtype B). We identified 107 patients with phylogenetic evidence for superinfection. In 14 of these cases, we analyzed newly amplified sequences from the original samples for validation purposes: only 2 cases were verified as superinfections in the repeated analyses, the other 12 cases turned out to involve sample or sequence misidentification. Resistance to drugs used at the time of strain replacement did not change in these two patients. A third case could not be validated by re-sequencing, but was supported as superinfection by an intermediate sequence with high degenerate base pair count within the time frame of strain switching. Drug resistance increased in this single patient.

Conclusions

Routine genotyping data are informative for the detection of HIV superinfection; however, most cases of non-monophyletic clustering in patient phylogenies arise from sample or sequence mix-up rather than from superinfection, which emphasizes the importance of validation. Non-transient superinfection was rare in our mainly treatment experienced cohort, and we found a single case of possible transmitted drug resistance by this route. We therefore conclude that in our large cohort, superinfection with drug resistant HIV did not compromise the efficiency of antiretroviral treatment.

Keywords:
HIV; Superinfection; Transmitted drug resistance; Sequence analysis