{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T03:52:10Z","timestamp":1791085930224,"version":"4.1.0"},"reference-count":40,"publisher":"Springer Science and Business Media LLC","issue":"3","license":[{"start":{"date-parts":[[2012,2,19]],"date-time":"2012-02-19T00:00:00Z","timestamp":1329609600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/www.springer.com\/tdm"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nat Med"],"published-print":{"date-parts":[[2012,3]]},"DOI":"10.1038\/nm.2649","type":"journal-article","created":{"date-parts":[[2012,2,19]],"date-time":"2012-02-19T13:07:25Z","timestamp":1329656845000},"page":"446-451","source":"Crossref","is-referenced-by-count":152,"title":["A quantitative basis for antiretroviral therapy for HIV-1 infection"],"prefix":"10.1038","volume":"18","author":[{"given":"Benjamin L","family":"Jilek","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa","family":"Zarr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maame E","family":"Sampah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S Alireza","family":"Rabi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cynthia K","family":"Bullen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Lai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert F","family":"Siliciano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2012,2,19]]},"reference":[{"key":"BFnm2649_CR1","doi-asserted-by":"publisher","first-page":"734","DOI":"10.1056\/NEJM199709113371102","volume":"337","author":"RM Gulick","year":"1997","unstructured":"Gulick, R.M. et al. Treatment with indinavir, zidovudine, and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy. N. Engl. J. Med. 337, 734\u2013739 (1997).","journal-title":"N. Engl. J. Med."},{"key":"BFnm2649_CR2","doi-asserted-by":"publisher","first-page":"725","DOI":"10.1056\/NEJM199709113371101","volume":"337","author":"SM Hammer","year":"1997","unstructured":"Hammer, S.M. et al. A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. AIDS Clinical Trials Group 320 Study Team. N. Engl. J. Med. 337, 725\u2013733 (1997).","journal-title":"N. Engl. J. Med."},{"key":"BFnm2649_CR3","doi-asserted-by":"publisher","first-page":"188","DOI":"10.1038\/387188a0","volume":"387","author":"AS Perelson","year":"1997","unstructured":"Perelson, A.S. et al. Decay characteristics of HIV-1-infected compartments during combination therapy. Nature 387, 188\u2013191 (1997).","journal-title":"Nature"},{"key":"BFnm2649_CR4","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1086\/505147","volume":"194","author":"RP Walensky","year":"2006","unstructured":"Walensky, R.P. et al. The survival benefits of AIDS treatment in the United States. J. Infect. Dis. 194, 11\u201319 (2006).","journal-title":"J. Infect. Dis."},{"key":"BFnm2649_CR5","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1038\/373117a0","volume":"373","author":"X Wei","year":"1995","unstructured":"Wei, X. et al. Viral dynamics in human immunodeficiency virus type 1 infection. Nature 373, 117\u2013122 (1995).","journal-title":"Nature"},{"key":"BFnm2649_CR6","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1038\/373123a0","volume":"373","author":"DD Ho","year":"1995","unstructured":"Ho, D.D. et al. Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature 373, 123\u2013126 (1995).","journal-title":"Nature"},{"key":"BFnm2649_CR7","doi-asserted-by":"publisher","first-page":"483","DOI":"10.1126\/science.7824947","volume":"267","author":"JM Coffin","year":"1995","unstructured":"Coffin, J.M. HIV population dynamics in vivo: implications for genetic variation, pathogenesis, and therapy. Science 267, 483\u2013489 (1995).","journal-title":"Science"},{"key":"BFnm2649_CR8","doi-asserted-by":"publisher","first-page":"1582","DOI":"10.1126\/science.271.5255.1582","volume":"271","author":"AS Perelson","year":"1996","unstructured":"Perelson, A.S., Neumann, A.U., Markowitz, M., Leonard, J.M. & Ho, D.D. HIV-1 dynamics in vivo: virion clearance rate, infected cell life-span and viral generation time. Science 271, 1582\u20131586 (1996).","journal-title":"Science"},{"key":"BFnm2649_CR9","doi-asserted-by":"publisher","first-page":"1178","DOI":"10.1002\/bies.10196","volume":"24","author":"D Wodarz","year":"2002","unstructured":"Wodarz, D. & Nowak, M.A. Mathematical models of HIV pathogenesis and treatment. Bioessays 24, 1178\u20131187 (2002).","journal-title":"Bioessays"},{"key":"BFnm2649_CR10","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1001\/jama.2010.1004","volume":"304","author":"MA Thompson","year":"2010","unstructured":"Thompson, M.A. et al. Antiretroviral treatment of adult HIV infection: 2010 recommendations of the International AIDS Society-USA panel. J. Am. Med. Assoc. 304, 321\u2013333 (2010).","journal-title":"J. Am. Med. Assoc."},{"key":"BFnm2649_CR11","unstructured":"Department of Health and Human Services Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1\u2013infected adults and adolescents. \u3008 http:\/\/www.aidsinfo.nih.gov\/ContentFiles\/AdultandAdolescentGL.pdf \u3009 (2009)."},{"key":"BFnm2649_CR12","doi-asserted-by":"publisher","first-page":"762","DOI":"10.1038\/nm1777","volume":"14","author":"L Shen","year":"2008","unstructured":"Shen, L. et al. Dose-response curve slope sets class-specific limits on inhibitory potential of anti-HIV drugs. Nat. Med. 14, 762\u2013766 (2008).","journal-title":"Nat. Med."},{"key":"BFnm2649_CR13","first-page":"4","volume":"40","author":"AV Hill","year":"1910","unstructured":"Hill, A.V. The possible effects of the aggregation of the molecules of huemoglobin on its dissociation curves. J. Physiol. (Lond.) 40, 4\u20137 (1910).","journal-title":"J. Physiol. (Lond.)"},{"key":"BFnm2649_CR14","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1016\/0022-5193(76)90169-7","volume":"59","author":"TC Chou","year":"1976","unstructured":"Chou, T.C. Derivation and properties of Michaelis-Menten type and Hill type equations for reference ligands. J. Theor. Biol. 59, 253\u2013276 (1976).","journal-title":"J. Theor. Biol."},{"key":"BFnm2649_CR15","doi-asserted-by":"publisher","first-page":"429","DOI":"10.2165\/00003088-198106060-00002","volume":"6","author":"NH Holford","year":"1981","unstructured":"Holford, N.H. & Sheiner, L.B. Understanding the dose-effect relationship: clinical application of pharmacokinetic-pharmacodynamic models. Clin. Pharmacokinet. 6, 429\u2013453 (1981).","journal-title":"Clin. Pharmacokinet."},{"key":"BFnm2649_CR16","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1016\/S0031-6997(25)06847-4","volume":"47","author":"WR Greco","year":"1995","unstructured":"Greco, W.R., Bravo, G. & Parsons, J.C. The search for synergy: a critical review from a response surface perspective. Pharmacol. Rev. 47, 331\u2013385 (1995).","journal-title":"Pharmacol. Rev."},{"key":"BFnm2649_CR17","doi-asserted-by":"publisher","first-page":"621","DOI":"10.1124\/pr.58.3.10","volume":"58","author":"TC Chou","year":"2006","unstructured":"Chou, T.C. Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacol. Rev. 58, 621\u2013681 (2006).","journal-title":"Pharmacol. Rev."},{"key":"BFnm2649_CR18","doi-asserted-by":"publisher","first-page":"7613","DOI":"10.1073\/pnas.1018360108","volume":"108","author":"ME Sampah","year":"2011","unstructured":"Sampah, M.E., Shen, L., Jilek, B.L. & Siliciano, R.F. Dose-response curve slope is a missing dimension in the analysis of HIV-1 drug resistance. Proc. Natl. Acad. Sci. USA 108, 7613\u20137618 (2011).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"BFnm2649_CR19","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1016\/S0165-6147(00)01615-1","volume":"22","author":"NM Ferguson","year":"2001","unstructured":"Ferguson, N.M., Fraser, C. & Anderson, R.M. Viral dynamics and anti-viral pharmacodynamics: rethinking in vitro measures of drug potency. Trends Pharmacol. Sci. 22, 97\u2013100 (2001).","journal-title":"Trends Pharmacol. Sci."},{"key":"BFnm2649_CR20","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1016\/0065-2571(84)90007-4","volume":"22","author":"TC Chou","year":"1984","unstructured":"Chou, T.C. & Talalay, P. Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv. Enzyme Regul. 22, 27\u201355 (1984).","journal-title":"Adv. Enzyme Regul."},{"key":"BFnm2649_CR21","doi-asserted-by":"publisher","first-page":"91ra63","DOI":"10.1126\/scitranslmed.3002304","volume":"3","author":"L Shen","year":"2011","unstructured":"Shen, L. et al. A critical subset model provides a conceptual basis for the high antiviral activity of major HIV drugs. Sci. Transl. Med. 3, 91ra63 (2011).","journal-title":"Sci. Transl. Med."},{"key":"BFnm2649_CR22","doi-asserted-by":"publisher","first-page":"2039","DOI":"10.1056\/NEJMoa012354","volume":"346","author":"S Walmsley","year":"2002","unstructured":"Walmsley, S. et al. Lopinavir-ritonavir versus nelfinavir for the initial treatment of HIV infection. N. Engl. J. Med. 346, 2039\u20132046 (2002).","journal-title":"N. Engl. J. Med."},{"key":"BFnm2649_CR23","first-page":"491","volume":"5","author":"JD Siliciano","year":"2010","unstructured":"Siliciano, J.D. & Siliciano, R.F. Biomarkers of HIV replication. Curr. Opin. HIV. AIDS 5, 491\u2013497 (2010).","journal-title":"AIDS"},{"key":"BFnm2649_CR24","doi-asserted-by":"crossref","first-page":"2365","DOI":"10.1097\/QAD.0b013e32833dec20","volume":"24","author":"C Katlama","year":"2010","unstructured":"Katlama, C. et al. Efficacy of darunavir\/ritonavir maintenance monotherapy in patients with HIV-1 viral suppression: a randomized open-label, noninferiority trial, MONOI-ANRS 136. AIDS 24, 2365\u20132374 (2010).","journal-title":"AIDS"},{"key":"BFnm2649_CR25","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1097\/QCO.0b013e3283422cdf","volume":"24","author":"I Per\u00e9z-Valero","year":"2011","unstructured":"Per\u00e9z-Valero, I. & Arribas, J.R. Protease inhibitor monotherapy. Curr. Opin. Infect. Dis. 24, 7\u201311 (2011).","journal-title":"Curr. Opin. Infect. Dis."},{"key":"BFnm2649_CR26","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1097\/QAD.0b013e32831c54e5","volume":"23","author":"WF Bierman","year":"2009","unstructured":"Bierman, W.F., van Agtmael, M.A., Nijhuis, M., Danner, S.A. & Boucher, C.A. HIV monotherapy with ritonavir-boosted protease inhibitors: a systematic review. AIDS 23, 279\u2013291 (2009).","journal-title":"AIDS"},{"key":"BFnm2649_CR27","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1097\/QAI.0b013e318157131c","volume":"46","author":"M Markowitz","year":"2007","unstructured":"Markowitz, M. et al. Rapid and durable antiretroviral effect of the HIV-1 Integrase inhibitor raltegravir as part of combination therapy in treatment-naive patients with HIV-1 infection: results of a 48-week controlled study. J. Acquir. Immune Defic. Syndr. 46, 125\u2013133 (2007).","journal-title":"J. Acquir. Immune Defic. Syndr."},{"key":"BFnm2649_CR28","doi-asserted-by":"publisher","first-page":"803","DOI":"10.1086\/650697","volume":"201","author":"DA Cooper","year":"2010","unstructured":"Cooper, D.A. et al. Maraviroc versus efavirenz, both in combination with zidovudine-lamivudine, for the treatment of antiretroviral-naive subjects with CCR5-tropic HIV-1 infection. J. Infect. Dis. 201, 803\u2013813 (2010).","journal-title":"J. Infect. Dis."},{"key":"BFnm2649_CR29","doi-asserted-by":"publisher","first-page":"585","DOI":"10.1111\/j.1744-7348.1939.tb06990.x","volume":"26","author":"CI Bliss","year":"1939","unstructured":"Bliss, C.I. The toxicity of poisons jointly applied. Ann. Appl. Biol. 26, 585\u2013615 (1939).","journal-title":"Ann. Appl. Biol."},{"key":"BFnm2649_CR30","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1007\/BF01952257","volume":"114","author":"S Loewe","year":"1926","unstructured":"Loewe, S. & Muischnek, H. Effect of combinations: mathematical basis of problem. Arch. Exp. Pathol. Pharmakol. 114, 313\u2013326 (1926).","journal-title":"Arch. Exp. Pathol. Pharmakol."},{"key":"BFnm2649_CR31","doi-asserted-by":"publisher","first-page":"1783","DOI":"10.1126\/science.1377403","volume":"256","author":"LA Kohlstaedt","year":"1992","unstructured":"Kohlstaedt, L.A., Wang, J., Friedman, J.M., Rice, P.A. & Steitz, T.A. Crystal structure at 3.5 A resolution of HIV-1 reverse transcriptase complexed with an inhibitor. Science 256, 1783\u20131790 (1992).","journal-title":"Science"},{"key":"BFnm2649_CR32","doi-asserted-by":"publisher","first-page":"1231","DOI":"10.1128\/AAC.41.6.1231","volume":"41","author":"PG Hoggard","year":"1997","unstructured":"Hoggard, P.G., Kewn, S., Barry, M.G., Khoo, S.H. & Back, D.J. Effects of drugs on 2\u2032,3\u2032-dideoxy-2\u2032,3\u2032-didehydrothymidine phosphorylation in vitro. Antimicrob. Agents Chemother. 41, 1231\u20131236 (1997).","journal-title":"Antimicrob. Agents Chemother."},{"key":"BFnm2649_CR33","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1086\/315683","volume":"182","author":"DV Havlir","year":"2000","unstructured":"Havlir, D.V. et al. In vivo antagonism with zidovudine plus stavudine combination therapy. J. Infect. Dis. 182, 321\u2013325 (2000).","journal-title":"J. Infect. Dis."},{"key":"BFnm2649_CR34","doi-asserted-by":"publisher","first-page":"3429","DOI":"10.1128\/JVI.78.7.3429-3435.2004","volume":"78","author":"DJ Wyma","year":"2004","unstructured":"Wyma, D.J. et al. Coupling of human immunodeficiency virus type 1 fusion to virion maturation: a novel role of the gp41 cytoplasmic tail. J. Virol. 78, 3429\u20133435 (2004).","journal-title":"J. Virol."},{"key":"BFnm2649_CR35","doi-asserted-by":"publisher","first-page":"1026","DOI":"10.1128\/JVI.78.2.1026-1031.2004","volume":"78","author":"T Murakami","year":"2004","unstructured":"Murakami, T., Ablan, S., Freed, E.O. & Tanaka, Y. Regulation of human immunodeficiency virus type 1 Env-mediated membrane fusion by viral protease activity. J. Virol. 78, 1026\u20131031 (2004).","journal-title":"J. Virol."},{"key":"BFnm2649_CR36","doi-asserted-by":"publisher","first-page":"29692","DOI":"10.1074\/jbc.M109.027144","volume":"284","author":"B M\u00fcller","year":"2009","unstructured":"M\u00fcller, B. et al. HIV-1 Gag processing intermediates trans-dominantly interfere with HIV-1 infectivity. J. Biol. Chem. 284, 29692\u201329703 (2009).","journal-title":"J. Biol. Chem."},{"key":"BFnm2649_CR37","doi-asserted-by":"publisher","first-page":"796","DOI":"10.1016\/S0140-6736(09)60918-1","volume":"374","author":"JL Lennox","year":"2009","unstructured":"Lennox, J.L. et al. Safety and efficacy of raltegravir-based versus efavirenz-based combination therapy in treatment-naive patients with HIV-1 infection: a multicentre, double-blind randomised controlled trial. Lancet 374, 796\u2013806 (2009).","journal-title":"Lancet"},{"key":"BFnm2649_CR38","doi-asserted-by":"publisher","first-page":"1921","DOI":"10.1086\/498069","volume":"192","author":"JE Gallant","year":"2005","unstructured":"Gallant, J.E. et al. Early virologic nonresponse to tenofovir, abacavir, and lamivudine in HIV-infected antiretroviral-naive subjects. J. Infect. Dis. 192, 1921\u20131930 (2005).","journal-title":"J. Infect. Dis."},{"key":"BFnm2649_CR39","doi-asserted-by":"publisher","first-page":"1295","DOI":"10.1126\/science.278.5341.1295","volume":"278","author":"D Finzi","year":"1997","unstructured":"Finzi, D. et al. Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy. Science 278, 1295\u20131300 (1997).","journal-title":"Science"},{"key":"BFnm2649_CR40","doi-asserted-by":"publisher","first-page":"512","DOI":"10.1038\/8394","volume":"5","author":"D Finzi","year":"1999","unstructured":"Finzi, D. et al. Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy. Nat. Med. 5, 512\u2013517 (1999).","journal-title":"Nat. Med."}],"container-title":["Nature Medicine"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/www.nature.com\/articles\/nm.2649.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/www.nature.com\/articles\/nm.2649","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/www.nature.com\/articles\/nm.2649.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,21]],"date-time":"2025-03-21T01:49:43Z","timestamp":1742521783000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/nm.2649"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,2,19]]},"references-count":40,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2012,3]]}},"alternative-id":["BFnm2649"],"URL":"https:\/\/doi.org\/10.1038\/nm.2649","relation":{},"ISSN":["1078-8956","1546-170X"],"issn-type":[{"value":"1078-8956","type":"print"},{"value":"1546-170X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2012,2,19]]}}}