Superinfection with drug-resistant HIV is rare and does not contribute substantially to therapy failure in a large European cohort
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
BMC Infectious Diseases 2013, 13:537 doi:10.1186/1471-2334-13-537Published: 12 November 2013
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.
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.
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.
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.