Skip to main content

Mystery of HIV Drug Resistance: A Machine Learning Perspective

  • Chapter
  • First Online:
Global Virology III: Virology in the 21st Century

Abstract

Human immunodeficiency virus (HIV) is one of the fastest developing pathogens known. HIV/AIDS is an incurable disease which causes severe damage to the immune system. The recommended treatment for HIV/AIDS is a combination of three antiretroviral (ARV) drugs from two or more different drug groups and is known as highly active antiretroviral therapy (HAART). Drug resistance is a major impediment experienced by therapist in treating HIV infected patients. Theoretically, drug resistance can be predicted from the presence of specific mutations in the viral genome. With the current disease burden and lack of resources in developing countries, phenotypic tests are not viable. Developing a computational prediction of drug resistance phenotype will enable efficient and timely selection of the best treatment regimens. Nevertheless, the very large range of possible drug combinations and of viral mutational patterns leads to an extremely complex scenario, making prediction of in vivo treatment response extremely challenging. To deal with such complexity, machine learning methods are being increasingly explored. Clinical and technological developments has generated and stored large volumes of data in public databases which facilitates the use of machine learning methods for predicting drug resistance. Quite a lot of machine learning approaches such as neural networks, support vector machine, Bayesian networks, decision trees and linear regression have been proposed for the prediction of phenotypic drug resistance. Therefore, conducting resistance testing is certainly significant in order to administer appropriate antiviral drugs to HIV infected patients.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. World Health Organization.. HIV drug resistance report 2017. www.who.int/hiv/pub/drugresistance/hivdr-report-2017/en/.

  2. Kallings LO. The first postmodern pandemic: 25 years of HIV/AIDS. J Intern Med. 2008;263(3):218–43.

    Article  CAS  PubMed  Google Scholar 

  3. Beyrer C, Pozniak A. HIV drug resistance – an emerging threat to epidemic control. N Engl J Med. 2017;377(17):1605–7.

    Article  PubMed  Google Scholar 

  4. Greene WC. A history of AIDS: looking back to see ahead. Eur J Immunol Nov:2007. http://www.ncbi.nlm.nih.gov/pubmed/17972351/.

  5. Popovic M, Sarngadharan MG, Read E, Gallo RC. Detection, isolation, and continuous production of cytopathic retroviruses (HTLV-III) from patients with AIDS and pre-AIDS. Science. 1984;224(4648):497–500.

    Article  CAS  PubMed  Google Scholar 

  6. Shen C, Yu X, Harrison RW, Weber IT. Automated prediction of HIV drug resistance from genotype data. BMC Bioinf. 2016;17(Suppl 8):278.

    Article  CAS  Google Scholar 

  7. de Oliveira T, Shafer RW, Seebregts C. Public database for HIV drug resistance in southern Africa. Nature. 2010;464(7289):673.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. UK HIV Drug Resistance Database, UCL Institute for Global Health in London. Available at: http://www.hivrdb.org.uk.

  9. Stanford HIV drug resistance database. Available at: https://hivrdb.stanford.edu.

  10. Cordes F, Kaiser R, Selbig J. Bioinformatics approach to predicting HIV drug resistance. Expert Rev Mol Diagn. 2006;6(2):207–15.

    Article  CAS  PubMed  Google Scholar 

  11. Carvajal-Rodríguez A. The importance of bio-computational tools for predicting HIV drug resistance. Recent Pat DNA Gene Seq. 2007;1(1):63–8.

    Article  PubMed  Google Scholar 

  12. Prosperi MCF, De Luca A. Computational models for prediction of response to antiretroviral therapies. AIDS Rev. 2012;14(2):145–53.

    PubMed  Google Scholar 

  13. Durant J, et al. Drug-resistance genotyping in HIV-1 therapy: the VIRADAPT randomised controlled trial. Lancet. 1999;353(9171):2195–9.

    Article  CAS  PubMed  Google Scholar 

  14. Obermeyer Z, Emanuel EJ. Predicting the future – big data, machine learning, and clinical medicine. N Engl J Med. 2016;375(13):1216.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Yu, X. “HIV drug resistant prediction and featured mutants selection using machine learning approaches”. Dissertation, Georgia State University. 2014.

    Google Scholar 

  16. Singh Y, Mars M. Support vector machines to forecast changes in CD4 count of HIV-1 positive patients. Sci Res Essays. 2010;5(17):2384–90.

    Google Scholar 

  17. Goldbaum MH, Falkenstein I, Kozak I, Hao J, Bartsch DU, Sejnowski T, Freeman WR. Analysis with support vector machine shows HIV-positive subjects without infectious retinitis have MfERG deficiencies compared to normal eyes. Trans Am Ophthalmol Soc. 2008;106:196–204; discussion 204-5.

    PubMed  PubMed Central  Google Scholar 

  18. Singh Y, Narsai N, Mars M. Applying machine learning to predict patient-specific current CD 4 cell count in order to determine the progression of human immunodeficiency virus (HIV) infection. Afr J Biotechnol. 2013;12(23):3724–30.

    Google Scholar 

  19. Wang D, et al. A comparison of three computational modelling methods for the prediction of virological response to combination HIV therapy. Artif Intell Med. 2009;47(1):63–74.

    Article  PubMed  Google Scholar 

  20. Larder B, Wang D, Revell A. Application of artificial neural networks for decision support in medicine. Methods Mol Biol. 2008;458:123–36.

    PubMed  Google Scholar 

  21. Li Y, Rapkin B. Classification and regression tree uncovered hierarchy of psychosocial determinants underlying quality-of-life response shift in HIV/AIDS. J Clin Epidemiol. 2009;62(11):1138–47.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Munoz-Moreno JA, et al. Classification models for neurocognitive impairment in HIV infection based on demographic and clinical variables. PLoS One. 2014;9(9):e107625.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Choi I, et al. Machine learning methods enable predictive modeling of antibody feature: function relationships in RV144 vaccines. PLoS Comput Biol. 2015;11(4):e1004185.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Revell AD, et al. The use of computational models to predict response to HIV therapy for clinical cases in Romania. Germs. 2012;2(1):6.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Dietterich TG. Ensemble methods in machine learning. [cited 2016 30th/Aug/]; Available from: http://www.cs.orst.edu/~tgd.

  26. Bonet I, Rodríguez A, Grau Ábalo R, García MM, Saeys Y, Nowé A. In: Gelbukh A, Morales EF, editors. MICAI 2008, LNAI 5317: Comparing distance measures with visual methods. Berlin/Heidelberg: Springer; 2008. p. 90–9.

    Google Scholar 

  27. Jordan M, Mitchell T. Machine learning: trends, perspectives, and prospects. Science. 2015;349(6245):255–60.

    Article  CAS  PubMed  Google Scholar 

  28. White AD. Complexity of human immunodeficiency virus management in developing countries. Epidemiology. 1998;9(6):593–5.

    Article  CAS  PubMed  Google Scholar 

  29. Zhu X, Goldberg AB. Introduction to semi-supervised learning. Synth Lect Artif Intell Mach Learn. 2009;3(1):1–130.

    Article  Google Scholar 

  30. Tan P-n, Steinbach M, Kumar V. Introduction to data mining. New York: Pearson Education, Limited; 2014.

    Google Scholar 

  31. Yu X, Weber IT, Harrison RW. Prediction of HIV drug resistance from genotype with encoded three-dimensional protein structure. BMC Genomics. 2014;15(Suppl 5):S1.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Beerenwinkel N, et al. Diversity and complexity of HIV-1 drug resistance: a bioinformatics approach to predicting phenotype from genotype. Proc Natl Acad Sci U S A. 2002;99(12):8271–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Wang D, Larder B. Enhanced prediction of Lopinavir resistance from genotype by use of artificial neural networks. J Infect Dis. 2003;188(5):653–60.

    Article  PubMed  Google Scholar 

  34. Beerenwinkel N, et al. Geno2pheno: estimating phenotypic drug resistance from HIV-1 genotypes. Nucleic Acids Res. 2003;31(13):3850–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Deforche K, et al. Analysis of HIV-1 pol sequences using Bayesian networks: implications for drug resistance. Bioinformatics. 2006;22(24):2975–9.

    Article  CAS  PubMed  Google Scholar 

  36. Liu TF, Shafer RW. Web resources for HIV type 1 genotypic-resistance test interpretation. Clin Infect Dis. 2006;42(11):1608–18.

    Article  CAS  PubMed  Google Scholar 

  37. Obermeier M, et al. HIV-GRADE: a publicly available, rules-based drug resistance interpretation algorithm integrating bioinformatic knowledge. Intervirology. 2012;55(2):102–7.

    Article  CAS  PubMed  Google Scholar 

  38. Brun-Vezinet F, et al. Clinically relevant interpretation of genotype for resistance to abacavir. AIDS. 2003;17(12):1795–802.

    Article  CAS  PubMed  Google Scholar 

  39. Humphris-Narayanan E, Akiva E, Varela R, Ó Conchúir S, Kortemme T. Prediction of mutational tolerance in HIV-1 protease and reverse transcriptase using flexible backbone protein design. PLoS Comput Biol. 2012;8(8):e1002639.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Hastie T, Tibshirani R, Friedman J. The elements of statistical learning: data mining, inference, and prediction. New York: Springer; 2009.

    Book  Google Scholar 

  41. Perno CF, Bertoli A. Clinical cut-offs in the interpretation of phenotypic resistance. In: Geretti AM, editor. Antiretroviral Resistance in Clinical Practice. London: Mediscript; 2006.

    Google Scholar 

  42. Winters B, et al. Determination of clinically relevant cutoffs for HIV-1 phenotypic resistance estimates through a combined analysis of clinical trial and cohort data. J Acquir Immune Defic Syndr. 2008;48(1):26–34.

    Article  PubMed  Google Scholar 

  43. Bonet I. Machine learning for prediction of HIV drug resistance: a review. Curr Bioinforma. 2015;10(5):579–85.

    Article  CAS  Google Scholar 

  44. Vapnik VN. The nature of statistical learning theory. New York: Springer; 2000.

    Book  Google Scholar 

  45. Araya ST, Hazelhurst S. Support vector machine prediction of HIV1 drug resistance using the viral nucleotide patterns. Trans Roy Soc S Afr. 2009;64(1):62–72.

    Article  Google Scholar 

  46. Canu S, Grandvalet Y, Guigue V, Rakotomamonjy A. SVM and kernel methods MATLAB toolbox. Perception Systemes et Information. Rouen: INSA de Rouen; 2005.

    Google Scholar 

  47. The MathWorks Inc. http://www.mathworks.com.

  48. Pearl J, Gabbay DM, Smets P. Graphical models for probabilistic and causal reasoning, Handbook of defeasible reasoning and uncertainty management systems, Volume 1: quantified representation of uncertainty and imprecision. 1998;1:367–389.

    Chapter  Google Scholar 

  49. Heckerman D. A tutorial on learning with Bayesian networks. Learning in graphical models. Cambridge: MIT Press; 1999. p. 301–54.

    Google Scholar 

  50. Klingler TM, Brutlag DL. Discovering structural correlations in α-helices. Protein Sci. 1994;3(10):1847–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Shafer RW. Genotypic testing for human immunodeficiency virus type 1 drug resistance. Clin Microbiol Rev. 2002;15(2):247–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Beerenwinkel N, et al. Learning multiple evolutionary pathways from cross-sectional data. J Comput Biol. 2005;12:584–98.

    Article  CAS  PubMed  Google Scholar 

  53. Rumelhart DE, Hinton GE, Williams RJ. Learning internal representations by error propagation. In: Rumelhart DE, McClelland JL, editors. Parallel distributed processing: explorations in the microstructure of cognition. Cambridge: MIT Press; 1986. p. 318–62.

    Google Scholar 

  54. Tamura S, Tateishi M. Capabilities of a four-layered feedforward neural network: four layers versus three. IEEE Trans Neural Netw. 1997;8(2):251–5.

    Article  CAS  PubMed  Google Scholar 

  55. Hornik K, Stinchcombe M, White H. Multilayer feedforward networks are universal approximators. Neural Netw. 1989;2(5):359–66.

    Article  Google Scholar 

  56. Howard D, Beale M. Neural network toolbox, for use with MATLAB, User’s guide, version 4. Natick: The MathWorks Inc; 2000. p. 133–05.

    Google Scholar 

  57. Adeniyi DA, Wei Z, Yongquan Y. Automated web usage data mining and recommendation system using K-Nearest Neighbor (KNN) classification method. Appl Comput Inform. 2016;12(1):90–108.

    Article  Google Scholar 

  58. Agence Nationale de recherches sur le SIDA. http://www.hivfrenshresistance.org. Accessed 2 Feb 2013.

  59. Johnson VA, Calvez V, Gunthard HF, et al. Update of the drug resistance mutations in HIV-1. Top Antivir Med. 2013;21(1):6–14.

    PubMed  Google Scholar 

  60. Yashik S, Maurice M. Predicting a single HIV drug resistance measure from three international interpretation gold standards. Asian Pac J Trop Med. 2012;5(7):566–72.

    Article  CAS  PubMed  Google Scholar 

  61. Meynard JL, et al. Phenotypic or genotypic resistance testing for choosing antiretroviral therapy after treatment failure: a randomized trial. AIDS. 2002;16(5):727–36.

    Article  PubMed  Google Scholar 

  62. Van Laethem K, et al. A genotypic drug resistance interpretation algorithm that significantly predicts therapy response in HIV-1-infected patients. Antivir Ther. 2002;7(2):123–9.

    PubMed  Google Scholar 

  63. Ravela J, et al. HIV-1 protease and reverse transcriptase mutation patterns responsible for discordances between genotypic drug resistance interpretation algorithms. J Acquir Immune Defic Syndr. 2003;33(1):8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Rhee SY, et al. Human immunodeficiency virus reverse transcriptase and protease sequence database. Nucleic Acids Res. 2003;31(1):298–303.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Schmidt B, et al. Simple algorithm derived from a geno−/phenotypic database to predict HIV-1 protease inhibitor resistance. AIDS. 2000;14(12):1731–8.

    Article  CAS  PubMed  Google Scholar 

  66. Zazzi M, et al. Comparative evaluation of three computerized algorithms for prediction of antiretroviral susceptibility from HIV type 1 genotype. J Antimicrob Chemother. 2004;53(2):356–60.

    Article  CAS  PubMed  Google Scholar 

  67. Shenderovich MD, et al. Structure-based phenotyping predicts HIV-1 protease inhibitor resistance. Protein Sci. 2003;12(8):1706–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Jenwitheesuk E, Samudrala R. Improved prediction of HIV-1 protease-inhibitor binding energies by molecular dynamics simulations. BMC Struct Biol. 2003;3(1):2.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Cao ZW, et al. Computer prediction of drug resistance mutations in proteins. Drug Discov Today. 2005;10(7):521–9.

    Article  CAS  PubMed  Google Scholar 

  70. Jenwitheesuk E, Samudrala R. Prediction of HIV-1 protease inhibitor resistance using a protein-inhibitor flexible docking approach. Antivir Ther. 2005;10(1):157–66.

    CAS  PubMed  Google Scholar 

  71. Ravich VL, Masso M, Vaisman II. A combined sequence–structure approach for predicting resistance to the non-nucleoside HIV-1 reverse transcriptase inhibitor Nevirapine. Biophys Chem. 2011;153(2):168–72.

    Article  CAS  PubMed  Google Scholar 

  72. Masso M, Vaisman II. Sequence and structure based models of HIV-1 protease and reverse transcriptase drug resistance. BMC Genomics. 2013;14(Suppl 4):S3.

    Article  PubMed  PubMed Central  Google Scholar 

  73. Kellam P, Larder BA. Recombinant virus assay: a rapid, phenotypic assay for assessment of drug susceptibility of human immunodeficiency virus type 1 isolates. Antimicrob Agents Chemother. 1994;38(1):23–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Hertogs K, et al. A rapid method for simultaneous detection of phenotypic resistance to inhibitors of protease and reverse transcriptase in recombinant human immunodeficiency virus type 1 isolates from patients treated with antiretroviral drugs. Antimicrob Agents Chemother. 1998;42(2):269–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. de Mendoza C, et al. HIV-1 genotypic drug resistance interpretation rules – 2009 Spanish guidelines. AIDS Rev. 2009;11(1):39–51.

    PubMed  Google Scholar 

  76. Anta L, et al. Resistance to the most recent protease and non-nucleoside reverse transcriptase inhibitors across HIV-1 non-B subtypes. J Antimicrob Chemother. 2013;68(9):1994–2002.

    Article  CAS  PubMed  Google Scholar 

  77. ARCA AntiRetroScan. Available at: http://www.hivarca.net/hiv_resistance.asp.

  78. WebPSSM. Available at: http://indra.mullins.microbiol.washington.edu/webpssm/.

  79. Trophix (prediction of HIV-1 tropism). Available at: http://sourceforge.net/projects/trophix/.

  80. RDI HIV-TRePS. Available at: http://www.hivrdi.org/treps/login.php.

  81. The EuResist engine. Available at: http://engine.euresist.org.

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Mohanapriya Arumugam .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Arumugam, M., Ponnusamy, N., Sudhakaran, S.L., Sundararajan, V., Kangueane, P. (2019). Mystery of HIV Drug Resistance: A Machine Learning Perspective. In: Shapshak, P., et al. Global Virology III: Virology in the 21st Century. Springer, Cham. https://doi.org/10.1007/978-3-030-29022-1_9

Download citation

Publish with us

Policies and ethics