Abstract
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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References
Lucas, G.M., Chaisson, R.E. & Moore, R.D. Highly active antiretroviral therapy in a large urban clinic: risk factors for virologic failure and adverse drug reactions. Ann. Intern. Med. 131, 81–87 (1999).
Hawkins, T. Understanding and managing the adverse effects of antiretroviral therapy. Antiviral Res. 85, 201–209 (2010).
Richman, D.D. et al. The challenge of finding a cure for HIV infection. Science 323, 1304–1307 (2009).
Abdool Karim, Q. et al. Effectiveness and safety of tenofovir gel, an antiretroviral microbicide, for the prevention of HIV infection in women. Science 329, 1168–1174 (2010).
Jia, J. et al. Mechanisms of drug combinations: interaction and network perspectives. Nat. Rev. Drug Discov. 8, 111–128 (2009).
Fitzgerald, J.B., Schoeberl, B., Nielsen, U.B. & Sorger, P.K. Systems biology and combination therapy in the quest for clinical efficacy. Nat. Chem. Biol. 2, 458–466 (2006).
Borisy, A.A. et al. Systematic discovery of multicomponent therapeutics. Proc. Natl. Acad. Sci. USA 100, 7977–7982 (2003).
Lehar, J. et al. Synergistic drug combinations tend to improve therapeutically relevant selectivity. Nat. Biotechnol. 27, 659–666 (2009).
Wilson-Lingardo, L. et al. Deconvolution of combinatorial libraries for drug discovery: experimental comparison of pooling strategies. J. Med. Chem. 39, 2720–2726 (1996).
Severyn, B. et al. Parsimonious discovery of synergistic drug combinations. ACS Chem. Biol. 6, 1391–1398 (2011).
Kimpton, J. & Emerman, M. Detection of replication-competent and pseudotyped human immunodeficiency virus with a sensitive cell line on the basis of activation of an integrated beta-galactosidase gene. J. Virol. 66, 2232–2239 (1992).
Brass, A.L. et al. Identification of host proteins required for HIV infection through a functional genomic screen. Science 319, 921–926 (2008).
Bliss, C.I. The calculation of microbial assays. Bacteriol. Rev. 20, 243–258 (1956).
Hanley, T.M. & Viglianti, G.A. Nuclear receptor signaling inhibits HIV-1 replication in macrophages through multiple trans-repression mechanisms. J. Virol. 85, 10834–10850 (2011).
Russo, F.O., Patel, P.C., Ventura, A.M. & Pereira, C.A. HIV-1 long terminal repeat modulation by glucocorticoids in monocytic and lymphocytic cell lines. Virus Res. 64, 87–94 (1999).
Andrieu, J.M. & Lu, W. Long-term clinical, immunologic and virologic impact of glucocorticoids on the chronic phase of HIV infection. BMC Med. 2, 17 (2004).
Ulmer, A., Muller, M., Bertisch-Mollenhoff, B. & Frietsch, B. Low dose prednisolone reduces CD4+ T cell loss in therapy-naive HIV-patients without antiretroviral therapy. Eur. J. Med. Res. 10, 105–109 (2005).
Korba, B.E. et al. Nitazoxanide, tizoxanide and other thiazolides are potent inhibitors of hepatitis B virus and hepatitis C virus replication. Antiviral Res. 77, 56–63 (2008).
Rossignol, J.F., La Frazia, S., Chiappa, L., Ciucci, A. & Santoro, M.G. Thiazolides, a new class of anti-influenza molecules targeting viral hemagglutinin at the post-translational level. J. Biol. Chem. 284, 29798–29808 (2009).
Chou, T.C. Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacol. Rev. 58, 621–681 (2006).
Yeh, P., Tschumi, A.I. & Kishony, R. Functional classification of drugs by properties of their pairwise interactions. Nat. Genet. 38, 489–494 (2006).
Cavrois, M., De Noronha, C. & Greene, W.C. A sensitive and specific enzyme-based assay detecting HIV-1 virion fusion in primary T lymphocytes. Nat. Biotechnol. 20, 1151–1154 (2002).
Collins, S.R., Schuldiner, M., Krogan, N.J. & Weissman, J.S. A strategy for extracting and analyzing large-scale quantitative epistatic interaction data. Genome Biol. 7, R63 (2006).
Hazenberg, M.D. et al. Persistent immune activation in HIV-1 infection is associated with progression to AIDS. AIDS 17, 1881–1888 (2003).
Deeks, S.G. et al. Immune activation set point during early HIV infection predicts subsequent CD4+ T-cell changes independent of viral load. Blood 104, 942–947 (2004).
Giorgi, J.V. et al. Predictive value of immunologic and virologic markers after long or short duration of HIV-1 infection. J. Acquir. Immune Defic. Syndr. 29, 346–355 (2002).
Hunt, P.W. et al. Relationship between T cell activation and CD4+ T cell count in HIV-seropositive individuals with undetectable plasma HIV RNA levels in the absence of therapy. J. Infect. Dis. 197, 126–133 (2008).
Douek, D.C., Roederer, M. & Koup, R.A. Emerging concepts in the immunopathogenesis of AIDS. Annu. Rev. Med. 60, 471–484 (2009).
Eggena, M.P. et al. T cell activation in HIV-seropositive Ugandans: differential associations with viral load, CD4+ T cell depletion, and coinfection. J. Infect. Dis. 191, 694–701 (2005).
Deeks, S.G. HIV infection, inflammation, immunosenescence, and aging. Annu. Rev. Med. 62, 141–155 (2011).
Chahroudi, A., Bosinger, S.E., Vanderford, T.H., Paiardini, M. & Silvestri, G. Natural SIV hosts: showing AIDS the door. Science 335, 1188–1193 (2012).
Malo, N., Hanley, J.A., Cerquozzi, S., Pelletier, J. & Nadon, R. Statistical practice in high-throughput screening data analysis. Nat. Biotechnol. 24, 167–175 (2006).
Kutsch, O. et al. Bis-anthracycline antibiotics inhibit human immunodeficiency virus type 1 transcription. Antimicrob. Agents Chemother. 48, 1652–1663 (2004).
O'Doherty, U., Swiggard, W.J. & Malim, M.H. Human immunodeficiency virus type 1 spinoculation enhances infection through virus binding. J. Virol. 74, 10074–10080 (2000).
Butler, S.L., Hansen, M.S. & Bushman, F.D. A quantitative assay for HIV DNA integration in vivo. Nat. Med. 7, 631 (2001).
Smoot, M.E., Ono, K., Ruscheinski, J., Wang, P.L. & Ideker, T. Cytoscape 2.8: new features for data integration and network visualization. Bioinformatics 27, 431 (2011).
Petraitis, V. et al. Combination therapy in treatment of experimental pulmonary aspergillosis: in vitro and in vivo correlations of the concentration- and dose- dependent interactions between anidulafungin and voriconazole by Bliss independence drug interaction analysis. Antimicrob. Agents Chemother. 53, 2382–2391 (2009).
Acknowledgements
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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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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Supplementary Figures 1–18 (PDF 21779 kb)
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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). https://doi.org/10.1038/nbt.2391
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DOI: https://doi.org/10.1038/nbt.2391
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