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A systems analysis of mutational effects in HIV-1 protease and reverse transcriptase


The development of a quantitative understanding of viral evolution and the fitness landscape in HIV-1 drug resistance is a formidable challenge given the large number of available drugs and drug resistance mutations. We analyzed a dataset measuring the in vitro fitness of 70,081 virus samples isolated from HIV-1 subtype B infected individuals undergoing routine drug resistance testing. We assayed virus samples for in vitro replicative capacity in the absence of drugs as well as in the presence of 15 individual drugs. We employed a generalized kernel ridge regression to estimate main fitness effects and epistatic interactions of 1,859 single amino acid variants found within the HIV-1 protease and reverse transcriptase sequences. Models including epistatic interactions predict an average of 54.8% of the variance in replicative capacity across the 16 different environments and substantially outperform models based on main fitness effects only. We find that the fitness landscape of HIV-1 protease and reverse transcriptase is characterized by strong epistasis.

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Figure 1: Analysis of predictive power.
Figure 2: Analysis of predictive power of different epistatic models for four representative environments.
Figure 3: Cumulative strength (CS) of the absolute epistatic effects in the HIV-1 protease as measured in the drug-free environment.


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T.H., J.M. and S.B. thank the Swiss National Science Foundation (NF 3100A0-116408) for financial support. We thank R. Regös, R. Kouyos, J. Engelstädter, S. Alizon and T. Gernhard-Stadler for valuable comments and critical reading of the manuscript.

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Authors and Affiliations



T.H. developed and implemented the generalized kernel ridge regression and analyzed data. J.M. analyzed data. C.C., M.H., E.S., J.M.W. and C.J.P. generated and pre-processed the experimental data. S.B. designed the study and analyzed data. T.H. and S.B. wrote the paper.

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Correspondence to Christos J Petropoulos or Sebastian Bonhoeffer.

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Competing interests

C.C., M.H., E.S., J.M.W. and C.J.P. are or have been employees of Monogram BioSciences and are named inventors on US and foreign patents held by Monogram BioSciences. S.B. is a consultant of Monogram BioSciences.

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Hinkley, T., Martins, J., Chappey, C. et al. A systems analysis of mutational effects in HIV-1 protease and reverse transcriptase. Nat Genet 43, 487–489 (2011).

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