title: A genotypic method for determining HIV-2 coreceptor usage enables epidemiological studies and clinical decision support.
abstract: BACKGROUND
  CCR5-coreceptor antagonists can be used for treating HIV-2 infected individuals. Before initiating treatment with coreceptor antagonists, viral coreceptor usage should be determined to ensure that the virus can use only the CCR5 coreceptor (R5) and cannot evade the drug by using the CXCR4 coreceptor (X4-capable). However, until now, no online tool for the genotypic identification of HIV-2 coreceptor usage had been available. Furthermore, there is a lack of knowledge on the determinants of HIV-2 coreceptor usage. Therefore, we developed a data-driven web service for the prediction of HIV-2 coreceptor usage from the V3 loop of the HIV-2 glycoprotein and used the tool to identify novel discriminatory features of X4-capable variants.
  
  
  RESULTS
  Using 10 runs of tenfold cross validation, we selected a linear support vector machine (SVM) as the model for geno2pheno[coreceptor-hiv2], because it outperformed the other SVMs with an area under the ROC curve (AUC) of 0.95. We found that SVMs were highly accurate in identifying HIV-2 coreceptor usage, attaining sensitivities of 73.5% and specificities of 96% during tenfold nested cross validation. The predictive performance of SVMs was not significantly different (p value 0.37) from an existing rules-based approach. Moreover, geno2pheno[coreceptor-hiv2] achieved a predictive accuracy of 100% and outperformed the existing approach on an independent data set containing nine new isolates with corresponding phenotypic measurements of coreceptor usage. geno2pheno[coreceptor-hiv2] could not only reproduce the established markers of CXCR4-usage, but also revealed novel markers: the substitutions 27K, 15G, and 8S were significantly predictive of CXCR4 usage. Furthermore, SVMs trained on the amino-acid sequences of the V1 and V2 loops were also quite accurate in predicting coreceptor usage (AUCs of 0.84 and 0.65, respectively).
  
  
  CONCLUSIONS
  In this study, we developed geno2pheno[coreceptor-hiv2], the first online tool for the prediction of HIV-2 coreceptor usage from the V3 loop. Using our method, we identified novel amino-acid markers of X4-capable variants in the V3 loop and found that HIV-2 coreceptor usage is also influenced by the V1/V2 region. The tool can aid clinicians in deciding whether coreceptor antagonists such as maraviroc are a treatment option and enables epidemiological studies investigating HIV-2 coreceptor usage. geno2pheno[coreceptor-hiv2] is freely available at http://coreceptor-hiv2.geno2pheno.org .
authors.affiliation: Department for Computational Biology and Applied Algorithmics, Max Planck Institute for Informatics, Saarland Informatics Campus, Campus E 1 4, 66123, Saarbrücken, Germany. mdoering@mpi-inf.mpg.de.
authors.forename: Matthias
authors.identifier: http://orcid.org/0000-0002-4261-9210
authors.initials: M
authors.lastname: Döring
authors.affiliation: Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, University of Lisbon, Av. Professor Gama Pinto, 1649-003, Lisbon, Portugal.|Centro de Administração e Políticas Públicas (CAPP), Instituto Superior de Ciências Sociais e Políticas (ISCSP), University of Lisbon, Rua Almerindo Lessa, 1300-663, Lisbon, Portugal.
authors.forename: Pedro
authors.initials: P
authors.lastname: Borrego
authors.affiliation: Department for Computational Biology and Applied Algorithmics, Max Planck Institute for Informatics, Saarland Informatics Campus, Campus E 1 4, 66123, Saarbrücken, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Büch
authors.affiliation: Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, University of Lisbon, Av. Professor Gama Pinto, 1649-003, Lisbon, Portugal.
authors.forename: Andreia
authors.initials: A
authors.lastname: Martins
authors.affiliation: Department for Computational Biology and Applied Algorithmics, Max Planck Institute for Informatics, Saarland Informatics Campus, Campus E 1 4, 66123, Saarbrücken, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Friedrich
authors.affiliation: Rega Institute for Medical Research, Clinical and Epidemiological Virology, Department of Microbiology and Immunology, KU Leuven-University of Leuven, Minderbroedersstraat 10, 3000, Louvain, Belgium.
authors.forename: Ricardo Jorge
authors.initials: RJ
authors.lastname: Camacho
authors.affiliation: Department of Virology, Max von Pettenkofer-Institut, Ludwig-Maximilians-University, Pettenkoferstraße 9a, 80336, Munich, Germany.
authors.forename: Josef
authors.initials: J
authors.lastname: Eberle
authors.affiliation: Institute for Virology, University of Cologne, Fürst-Pückler-Str. 56, 50935, Cologne, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Kaiser
authors.affiliation: Department for Computational Biology and Applied Algorithmics, Max Planck Institute for Informatics, Saarland Informatics Campus, Campus E 1 4, 66123, Saarbrücken, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Lengauer
authors.affiliation: Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, University of Lisbon, Av. Professor Gama Pinto, 1649-003, Lisbon, Portugal.|Instituto Superior de Ciências da Saúde Egas Moniz (ISCSEM), Campus Universitário, Quinta da Granja, Monte de Caparica, 2829-511, Caparica, Portugal.
authors.forename: Nuno
authors.initials: N
authors.lastname: Taveira
authors.affiliation: Department for Computational Biology and Applied Algorithmics, Max Planck Institute for Informatics, Saarland Informatics Campus, Campus E 1 4, 66123, Saarbrücken, Germany. npfeifer@mpi-inf.mpg.de.
authors.forename: Nico
authors.initials: N
authors.lastname: Pfeifer
mesh_terms: D065100:CCR5 Receptor Antagonists / Q000627:therapeutic use; D020000:Decision Support Systems, Clinical; D005838:Genotype; D060005:Genotyping Techniques; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000235:genetics*; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology*; D015498:HIV-2 / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D020407:Internet; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics*; D019713:Receptors, CCR5 / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism*; D060388:Support Vector Machine
chemical_list: D065100:CCR5 Receptor Antagonists; C584933:CCR5 protein, human; C527276:CXCR4 protein, human; D015699:HIV Envelope Protein gp120; C059762:HIV envelope protein gp120 (305-321); D010446:Peptide Fragments; D019713:Receptors, CCR5; D019718:Receptors, CXCR4
keywords: Chemokine receptor; Coreceptor; Coreceptor antagonists; HIV-2; Human immunodeficiency virus type 2; Prediction; Statistical learning; V1; V2; V3