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dc.creatorSedaghat, Ahmad R.en_US
dc.creatorWilke, Claus O.en_US
dc.date.accessioned2016-10-28T19:52:37Z
dc.date.available2016-10-28T19:52:37Z
dc.date.issued2011-09en_US
dc.identifierdoi:10.15781/T2R49GC3V
dc.identifier.citationSedaghat, Ahmad R., and Claus O. Wilke. "Kinetics of the viral cycle influence pharmacodynamics of antiretroviral therapy." Biol Direct, Vol. 6 (Sep., 2011): 42.en_US
dc.identifier.issn1745-6150en_US
dc.identifier.urihttp://hdl.handle.net/2152/43302
dc.description.abstractBackground: More and more antiretroviral therapies are being developed for treatment of HIV infection. The in-vivo efficacy of these drugs is commonly predicted based on in-vitro measures of antiviral effect. One primary invitro measure is the IC50, the amount of drug required for 50% inhibition of viral replication. We have previously shown that HIV life-cycle kinetics impact clinically observed HIV viral dynamics. Here we present a mathematical model of how they affect the pharmacodynamics of antiretroviral drugs. Results: We find that experimentally measured antiretroviral IC50s are determined by three factors: (i) intrinsic drug properties (e. g. drug-target binding), (ii) kinetics of the HIV life cycle, and (iii) kinetics of drug-inhibited infected cells. Our model predicts that the IC50 is a declining function of the duration of the drug-susceptible stage in the host cell. We combine our model with known viral life-cycle kinetics to derive a measure of intrinsic properties, reflecting drug action, for known antiretroviral drugs from previously measured IC50s. We show that this measure of intrinsic drug property correlates very well with in vitro-measured antiviral activity, whereas experimentally measured IC50 does not. Conclusions: Our results have implications for understanding pharmacodynamics of and improving activity of antiretroviral drugs. Our findings predict that drug activity can be improved through co-administration of synergistic drugs that delay the viral life cycle but are not inhibitory by themselves. Moreover, our results may easily extend to treatment of other pathogens.en_US
dc.description.sponsorshipNIH R01 GM088344en_US
dc.language.isoEnglishen_US
dc.relation.ispartofen_US
dc.rightsAdministrative deposit of works to Texas ScholarWorks: This works author(s) is or was a University faculty member, student or staff member; this article is already available through open access or the publisher allows a PDF version of the article to be freely posted online. The library makes the deposit as a matter of fair use (for scholarly, educational, and research purposes), and to preserve the work and further secure public access to the works of the University.en_US
dc.subjecthiven_US
dc.subjectviral dynamicsen_US
dc.subjecthaarten_US
dc.subjectantiretroviral therapyen_US
dc.subjectviral life cycleen_US
dc.subjectpharmacodynamicsen_US
dc.subjectic50en_US
dc.subjecthuman-immunodeficiency-virusen_US
dc.subjectin-vitroen_US
dc.subjectreverse-transcriptaseen_US
dc.subjectproteaseen_US
dc.subjectinhibitorsen_US
dc.subjectdrug susceptibilityen_US
dc.subjectclearance rateen_US
dc.subjecthiven_US
dc.subjecttype-1en_US
dc.subjectdynamicsen_US
dc.subjectreplicationen_US
dc.subjectbiologyen_US
dc.titleKinetics of the Viral Cycle Influence Pharmacodynamics of Antiretroviral Therapyen_US
dc.typeArticleen_US
dc.description.departmentCellular and Molecular Biologyen_US
dc.rights.restrictionOpenen_US
dc.identifier.doi10.1186/1745-6150-6-42en_US
dc.contributor.utaustinauthorWilke, Claus O.en_US
dc.relation.ispartofserialBiology Directen_US


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