Drug-Class Specific Impact of Antivirals on the Reproductive Capacity of HIV
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{"title"=>"Drug-class specific impact of antivirals on the reproductive capacity of HIV", "type"=>"journal", "authors"=>[{"first_name"=>"Max", "last_name"=>"von Kleist", "scopus_author_id"=>"15046062000"}, {"first_name"=>"Stephan", "last_name"=>"Menz", "scopus_author_id"=>"36116919100"}, {"first_name"=>"Wilhelm", "last_name"=>"Huisinga", "scopus_author_id"=>"56021154900"}], "year"=>2010, "source"=>"PLoS Computational Biology", "identifiers"=>{"scopus"=>"2-s2.0-77950829090", "doi"=>"10.1371/journal.pcbi.1000720", "pui"=>"358620645", "issn"=>"1553734X", "pmid"=>"20361047", "isbn"=>"1553-7358 (Electronic)\\r1553-734X (Linking)", "sgr"=>"77950829090"}, "id"=>"9c694247-62ae-3ecb-8cb0-02e2276eb883", "abstract"=>"Predictive markers linking drug efficacy to clinical outcome are a key component in the drug discovery and development process. In HIV infection, two different measures, viral load decay and phenotypic assays, are used to assess drug efficacy in vivo and in vitro. For the newly introduced class of integrase inhibitors, a huge discrepancy between these two measures of efficacy was observed. Hence, a thorough understanding of the relation between these two measures of drug efficacy is imperative for guiding future drug discovery and development activities in HIV. In this article, we developed a novel viral dynamics model, which allows for a mechanistic integration of the mode of action of all approved drugs and drugs in late clinical trials. Subsequently, we established a link between in vivo and in vitro measures of drug efficacy, and extract important determinants of drug efficacy in vivo. The analysis is based on a new quantity-the reproductive capacity-that represents in mathematical terms the in vivo analog of the read-out of a phenotypic assay. Our results suggest a drug-class specific impact of antivirals on the total amount of viral replication. Moreover, we showed that the (drug-)target half life, dominated by immune-system related clearance processes, is a key characteristic that affects both the emergence of resistance as well as the in vitro-in vivo correlation of efficacy measures in HIV treatment. We found that protease- and maturation inhibitors, due to their target half-life, decrease the total amount of viral replication and the emergence of resistance most efficiently.", "link"=>"http://www.mendeley.com/research/drugclass-specific-impact-antivirals-reproductive-capacity-hiv", "reader_count"=>24, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>1, "Researcher"=>9, "Student > Ph. D. Student"=>8, "Student > Postgraduate"=>2, "Student > Master"=>3, "Professor"=>1}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>1, "Researcher"=>9, "Student > Ph. D. Student"=>8, "Student > Postgraduate"=>2, "Student > Master"=>3, "Professor"=>1}, "reader_count_by_subject_area"=>{"Engineering"=>2, "Unspecified"=>3, "Mathematics"=>4, "Agricultural and Biological Sciences"=>10, "Medicine and Dentistry"=>3, "Pharmacology, Toxicology and Pharmaceutical Science"=>1, "Computer Science"=>1}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>2}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>3}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>10}, "Computer Science"=>{"Computer Science"=>1}, "Mathematics"=>{"Mathematics"=>4}, "Unspecified"=>{"Unspecified"=>3}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>1}}, "reader_count_by_country"=>{"United States"=>2, "Japan"=>1, "Brazil"=>1, "Germany"=>2}, "group_count"=>0}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/856267"], "description"=>"<p>Detailed structural model of the viral life cycle and the mechanisms of action of different anti-retroviral drug classes.</p>", "links"=>[], "tags"=>["viral", "mechanisms", "anti-retroviral"], "article_id"=>526720, "categories"=>["Medicine", "Pharmacology", "Infectious Diseases", "Virology"], "users"=>["Max von Kleist", "Stephan Menz", "Wilhelm Huisinga"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1000720.g001", "stats"=>{"downloads"=>1, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Detailed_structural_model_of_the_viral_life_cycle_and_the_mechanisms_of_action_of_different_anti_retroviral_drug_classes_/526720", "title"=>"Detailed structural model of the viral life cycle and the mechanisms of action of different anti-retroviral drug classes.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-03-26 01:52:00"}
  • {"files"=>["https://ndownloader.figshare.com/files/856854"], "description"=>"<p>The time to virological rebound depends on both the cost of resistance (‘selective disadvantage’, ) and the choice of drugs. Each table entry shows the time to virological rebound in [days] in an ensemble of hybrid stochastic deterministic simulations, where we assumed that the efficacy of the drugs against the wild type was . The drug was effective against an one-mutation strain and completely inefficient against the double-mutant. The fraction of non-infectious viruses () was set to one-third and the initial population was assumed to be all wild type. The viral load was said to be rebounded, if the viral load reached 90% of the pre-treatment viral load.</p>", "links"=>[], "tags"=>["rebound", "times", "resulting", "virological"], "article_id"=>527308, "categories"=>["Medicine", "Pharmacology", "Infectious Diseases", "Virology"], "users"=>["Max von Kleist", "Stephan Menz", "Wilhelm Huisinga"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1000720.t002", "stats"=>{"downloads"=>1, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Virological_rebound_times_resulting_from_distinct_virological_removal_/527308", "title"=>"Virological rebound times resulting from distinct virological removal.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2010-03-26 02:01:48"}
  • {"files"=>["https://ndownloader.figshare.com/files/856812"], "description"=>"<p>All parameters in units [1/day], except (unit less) and in . parameters chosen to reproduce clinical data. chosen according to the assumption that and utilizing parameters and to determine .</p>", "links"=>[], "tags"=>["parameters"], "article_id"=>527274, "categories"=>["Medicine", "Pharmacology", "Infectious Diseases", "Virology"], "users"=>["Max von Kleist", "Stephan Menz", "Wilhelm Huisinga"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1000720.t001", "stats"=>{"downloads"=>0, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Model_parameters_generally_used_in_simulations_/527274", "title"=>"Model parameters generally used in simulations.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2010-03-26 02:01:14"}
  • {"files"=>["https://ndownloader.figshare.com/files/856372"], "description"=>"<p>Ratios are affected through treatment with different drug classes. Predictions are based on the detailed model (see <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1000720#pcbi-1000720-g001\" target=\"_blank\">Fig. 1</a>) and mechanistic effect varying from 0–1. Chosen parameter values: </p>", "links"=>[], "tags"=>["classes", "viral", "infective"], "article_id"=>526824, "categories"=>["Medicine", "Pharmacology", "Infectious Diseases", "Virology"], "users"=>["Max von Kleist", "Stephan Menz", "Wilhelm Huisinga"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1000720.g002", "stats"=>{"downloads"=>1, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Mechanistic_effects_of_drug_classes_on_viral_infective_compartments_/526824", "title"=>"Mechanistic effects of drug classes on viral infective compartments.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-03-26 01:53:44"}
  • {"files"=>["https://ndownloader.figshare.com/files/425719", "https://ndownloader.figshare.com/files/425926"], "description"=>"<div><p>Predictive markers linking drug efficacy to clinical outcome are a key component in the drug discovery and development process. In HIV infection, two different measures, viral load decay and phenotypic assays, are used to assess drug efficacy <em>in vivo</em> and <em>in vitro</em>. For the newly introduced class of integrase inhibitors, a huge discrepancy between these two measures of efficacy was observed. Hence, a thorough understanding of the relation between these two measures of drug efficacy is imperative for guiding future drug discovery and development activities in HIV. In this article, we developed a novel viral dynamics model, which allows for a mechanistic integration of the mode of action of all approved drugs and drugs in late clinical trials. Subsequently, we established a link between <em>in vivo</em> and <em>in vitro</em> measures of drug efficacy, and extract important determinants of drug efficacy <em>in vivo</em>. The analysis is based on a new quantity—the reproductive capacity—that represents in mathematical terms the <em>in vivo</em> analog of the read-out of a phenotypic assay. Our results suggest a drug-class specific impact of antivirals on the total amount of viral replication. Moreover, we showed that the (drug-)target half life, dominated by immune-system related clearance processes, is a key characteristic that affects both the emergence of resistance as well as the <em>in vitro</em>–<em>in vivo</em> correlation of efficacy measures in HIV treatment. We found that protease- and maturation inhibitors, due to their target half-life, decrease the total amount of viral replication and the emergence of resistance most efficiently.</p></div>", "links"=>[], "tags"=>["drug-class", "antivirals", "reproductive", "hiv"], "article_id"=>144053, "categories"=>["Medicine", "Pharmacology", "Cancer"], "users"=>["Max von Kleist", "Stephan Menz", "Wilhelm Huisinga"], "doi"=>["https://dx.doi.org/10.1371/journal.pcbi.1000720.s001", "https://dx.doi.org/10.1371/journal.pcbi.1000720.s002"], "stats"=>{"downloads"=>11, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Drug_Class_Specific_Impact_of_Antivirals_on_the_Reproductive_Capacity_of_HIV/144053", "title"=>"Drug-Class Specific Impact of Antivirals on the Reproductive Capacity of HIV", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2010-03-26 01:07:33"}
  • {"files"=>["https://ndownloader.figshare.com/files/856719"], "description"=>"<p>A: Decay of infective compartments after treatment with FI and CCR5-antagonists. B: Decay of infective compartments after treatment with NRTIs and NNRTIs. C: Decay of infective compartments after treatment with InIs. D: Decay of infective compartments after treatment with PIs.</p>", "links"=>[], "tags"=>["infective", "compartments", "initiation"], "article_id"=>527176, "categories"=>["Medicine", "Pharmacology", "Infectious Diseases", "Virology"], "users"=>["Max von Kleist", "Stephan Menz", "Wilhelm Huisinga"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1000720.g006", "stats"=>{"downloads"=>4, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Decay_of_infective_compartments_after_initiation_of_drug_treatment_/527176", "title"=>"Decay of infective compartments after initiation of drug treatment.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-03-26 01:59:36"}
  • {"files"=>["https://ndownloader.figshare.com/files/856590"], "description"=>"<p>A: General transition pathways between wild type (00) and a fully drug resistant strain (11) that involves two partly-resistant intermediates (). B: Fitness in the presence of a drug. C: Fitness in the absence of drugs. Dashed line: critical fitness that allows the strain to survive, i.e, .</p>", "links"=>[], "tags"=>["mutational"], "article_id"=>527050, "categories"=>["Medicine", "Pharmacology", "Infectious Diseases", "Virology"], "users"=>["Max von Kleist", "Stephan Menz", "Wilhelm Huisinga"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1000720.g004", "stats"=>{"downloads"=>1, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Fitness_and_possible_mutational_pathways_/527050", "title"=>"Fitness and possible mutational pathways.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-03-26 01:57:30"}
  • {"files"=>["https://ndownloader.figshare.com/files/856639"], "description"=>"<p>A: Plasma virus load decay after treatment initiation. Integrase inhibitors (InI) produce a faster decay of virus load than all other compound classes. Red solid-, black dotted-, green dash-dotted- and blue dashed lines indicate simulation results with different inhibitor classes and parameters from <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1000720#pcbi-1000720-t001\" target=\"_blank\">Table 1</a>. Black diamonds indicate median viral load data from <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1000720#pcbi.1000720-Perelson1\" target=\"_blank\">[27]</a> (PI monotherapy), numerically available in <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1000720#pcbi.1000720-Rong2\" target=\"_blank\">[70]</a>. Black squares and black bullets indicate median viral load data from <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1000720#pcbi.1000720-Murray1\" target=\"_blank\">[21]</a> (NRTI + background therapy and InI+background therapy, respectively). The horizontal dashed black line indicates the limit of detection of current assays (50 copies of HIV RNA per mL). Inset: Protease- and maturation inhibitors (PI and MI) change the ratio of infectious to total virus (). B: The evolution of the reproductive capacity (evaluated at the drug free state ) after treatment with different drug classes. Model parameters are as indicated in <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1000720#pcbi-1000720-t001\" target=\"_blank\">Table 1</a>. The initial infection was assumed to consist of wild type only. Drug efficacy was assumed to be 100%. Total body virus has been converted to plasma viral load by assuming that the virus distributes into the plasma ( liters, which surrounds 2% of infected cells) and the interstitial space ( liters <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1000720#pcbi.1000720-Kawai1\" target=\"_blank\">[71]</a>, which surrounds 98% of infected cells). The volume of distribution with reference to the plasma concentration has been calculated using the well-known formula vol. distr , see e.g. <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1000720#pcbi.1000720-vonKleist2\" target=\"_blank\">[72]</a>, where . Finally, we assume that on average each virus contains 2 viral RNAs (which are measured [viral RNA/mL] plasma).</p>", "links"=>[], "tags"=>["viral", "reproductive"], "article_id"=>527096, "categories"=>["Medicine", "Pharmacology", "Infectious Diseases", "Virology"], "users"=>["Max von Kleist", "Stephan Menz", "Wilhelm Huisinga"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1000720.g005", "stats"=>{"downloads"=>0, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Decay_of_viral_load_and_reproductive_capacity_after_treatment_initiation_/527096", "title"=>"Decay of viral load and reproductive capacity after treatment initiation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-03-26 01:58:16"}
  • {"files"=>["https://ndownloader.figshare.com/files/856498"], "description"=>"<p>Species (red cycles), reactions (black arrows), drugs and their interference in the life cycle of HIV (blue dashed box). Target cells () can become successfully infected by infective virus with lumped infection rate constants and , respectively, creating early infected cells and . Infection can also be unsuccessful after the irreversible step of fusion (rate constant and ), eliminating the virus and rendering the cell uninfected. Early infected cells and can destroy essential viral proteins or DNA prior to integration with rate constants and returning the cell to an uninfected stage. The genomic viral DNA can become integrated with rate constants and creating late infected cells and , which can release new infectious- and non infectious virus and with rate constants and , respectively. Phenotypic mutation occurs at the stage of viral genomic integration (see section ‘Development of a simplified two stage virus dynamics model’). All cellular compartments can get destroyed by the immune system with respective rate constants and the free virus gets cleared with rate constant .</p>", "links"=>[], "tags"=>["computational biology/evolutionary modeling", "computational biology/systems biology", "infectious diseases/antimicrobials and drug resistance", "infectious diseases/hiv infection and aids", "pharmacology/drug development", "pharmacology/drug resistance", "virology/antivirals, including modes of action and resistance", "virology/immunodeficiency viruses", "virology/new therapies, including antivirals and immunotherapy"], "article_id"=>526949, "categories"=>["Medicine", "Pharmacology", "Infectious Diseases", "Virology"], "users"=>["Max von Kleist", "Stephan Menz", "Wilhelm Huisinga"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1000720.g003", "stats"=>{"downloads"=>1, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Simplified_two_stage_virus_dynamics_model_/526949", "title"=>"Simplified two stage virus dynamics model.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-03-26 01:55:49"}

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