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Systematic identification of synergistic drug pairs targeting HIV


The systematic identification of effective drug combinations has been hindered by the unavailability of methods that can explore the large combinatorial search space of drug interactions. Here we present multiplex screening for interacting compounds (MuSIC), which expedites the comprehensive assessment of pairwise compound interactions. We examined 500,000 drug pairs from 1,000 US Food and Drug Administration (FDA)-approved or clinically tested drugs and identified drugs that synergize to inhibit HIV replication. Our analysis reveals an enrichment of anti-inflammatory drugs in drug combinations that synergize against HIV. As inflammation accompanies HIV infection, these findings indicate that inhibiting inflammation could curb HIV propagation. Multiple drug pairs identified in this study, including various glucocorticoids and nitazoxanide (NTZ), synergize by targeting different steps in the HIV life cycle. MuSIC can be applied to a wide variety of disease-relevant screens to facilitate efficient identification of compound combinations.

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Figure 1: MuSIC strategy and screening assay.
Figure 2: MuSIC screen identified synergistic drug combinations.
Figure 3: Interactions with known anti-virals reveal drug mechanism.
Figure 4: Drug synergy network analysis reveals enrichments of drugs with known anti-HIV activity and anti-inflammatory functions.

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We thank the Institute of Chemistry and Cell Biology (ICCB)-Longwood: C. Shamu, S. Chiang, S. Rudnicki, A. Daab, D. Flood, S. Johnston, Z. Cooper, T. Ren; We also thank A. Brass for help with the HIV infection assay, N. Yan, Y. Koh, K. Matreyek and A. Engelman for help with virology, M. Mankowski for help with ELISA, M. Mefford for the BlaM assay protocol, NIH AIDS Research & Reference Reagent Program for reagents, J. Zhu, Q. Xu and other Elledge laboratory members for discussion and D. Fusco for reading the manuscript. X.T. is supported by the Damon Runyon Cancer Research Foundation (DRG 2008-09) and the Charles A. King Trust, N.A., Bank of America, co-trustee. Z.J.L. is supported by grants from the National Natural Science Foundation of China (31100601) and the National Key Basic Research Program (2012CB316503); S.J.E. is an investigator with the Howard Hughes Medical Institute.

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Authors and Affiliations



X.T. and S.J.E. designed the experiments, X.T., G.G. and H.Q. conducted experiments, L.J.L., R.X. and P.J.P. developed the algorithm of library construction, L.H., Y.L. and Z.J.L. performed bioinformatic analysis. P.J.P. and Z.J.L. contributed equally. All authors contributed to manuscript writing.

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Correspondence to Stephen J Elledge.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–18 (PDF 21779 kb)

Supplementary Tables

Supplementary Tables 1–8 (XLSX 3014 kb)

Supplementary Algorithm

MuSIC Heuristics (ZIP 13 kb)

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Tan, X., Hu, L., Luquette, L. et al. Systematic identification of synergistic drug pairs targeting HIV. Nat Biotechnol 30, 1125–1130 (2012).

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