Quantification system for the viral dynamics of a highly pathogenic simian/human immunodeficiency virus based on an in vitroexperiment and a mathematical model

Background Developing a quantitative understanding of viral kinetics is useful for determining the pathogenesis and transmissibility of the virus, predicting the course of disease, and evaluating the effects of antiviral therapy. The availability of data in clinical, animal, and cell culture studies, however, has been quite limited. Many studies of virus infection kinetics have been based solely on measures of total or infectious virus count. Here, we introduce a new mathematical model which tracks both infectious and total viral load, as well as the fraction of infected and uninfected cells within a cell culture, and apply it to analyze time-course data of an SHIV infection in vitro. Results We infected HSC-F cells with SHIV-KS661 and measured the concentration of Nef-negative (target) and Nef-positive (infected) HSC-F cells, the total viral load, and the infectious viral load daily for nine days. The experiments were repeated at four different MOIs, and the model was fitted to the full dataset simultaneously. Our analysis allowed us to extract an infected cell half-life of 14.1 h, a half-life of SHIV-KS661 infectiousness of 17.9 h, a virus burst size of 22.1 thousand RNA copies or 0.19 TCID50, and a basic reproductive number of 62.8. Furthermore, we calculated that SHIV-KS661 virus-infected cells produce at least 1 infectious virion for every 350 virions produced. Conclusions Our method, combining in vitro experiments and a mathematical model, provides detailed quantitative insights into the kinetics of the SHIV infection which could be used to significantly improve the understanding of SHIV and HIV-1 pathogenesis. The method could also be applied to other viral infections and used to improve the in vitro determination of the effect and efficacy of antiviral compounds.

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Quantification system for the viral dynamics of a highly pathogenic simian/human immunodeficiency virus based on an in vitroexperiment and a mathematical model

10.32920/14639370 ◽

2021 ◽

Author(s):

Shingo Iwami ◽

Benjamin P Holder ◽

Catherine A. A. Beauchemin ◽

Satoru Morita ◽

Tetsuko Tada ◽

...

Keyword(s):

Mathematical Model ◽

Cell Culture ◽

Viral Load ◽

Half Life ◽

Time Course ◽

Basic Reproductive Number ◽

Reproductive Number ◽

F Cells ◽

Shiv Infection

Background Developing a quantitative understanding of viral kinetics is useful for determining the pathogenesis and transmissibility of the virus, predicting the course of disease, and evaluating the effects of antiviral therapy. The availability of data in clinical, animal, and cell culture studies, however, has been quite limited. Many studies of virus infection kinetics have been based solely on measures of total or infectious virus count. Here, we introduce a new mathematical model which tracks both infectious and total viral load, as well as the fraction of infected and uninfected cells within a cell culture, and apply it to analyze time-course data of an SHIV infection in vitro. Results We infected HSC-F cells with SHIV-KS661 and measured the concentration of Nef-negative (target) and Nef-positive (infected) HSC-F cells, the total viral load, and the infectious viral load daily for nine days. The experiments were repeated at four different MOIs, and the model was fitted to the full dataset simultaneously. Our analysis allowed us to extract an infected cell half-life of 14.1 h, a half-life of SHIV-KS661 infectiousness of 17.9 h, a virus burst size of 22.1 thousand RNA copies or 0.19 TCID50, and a basic reproductive number of 62.8. Furthermore, we calculated that SHIV-KS661 virus-infected cells produce at least 1 infectious virion for every 350 virions produced. Conclusions Our method, combining in vitro experiments and a mathematical model, provides detailed quantitative insights into the kinetics of the SHIV infection which could be used to significantly improve the understanding of SHIV and HIV-1 pathogenesis. The method could also be applied to other viral infections and used to improve the in vitro determination of the effect and efficacy of antiviral compounds.

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1088. A Whole-Body Quantitative System Pharmacology Physiologically-Based Pharmacokinetic (QSP/PBPK) Model to Support Dose Selection of ADG20: an Extended Half-Life Monoclonal Antibody Being Developed for the Treatment of Coronavirus Disease (COVID-19)

Open Forum Infectious Diseases ◽

10.1093/ofid/ofab466.1282 ◽

2021 ◽

Vol 8 (Supplement_1) ◽

pp. S635-S635

Author(s):

Evan D Tarbell ◽

Scott A Van Wart ◽

Dhaval K Shah ◽

Laura M Walker ◽

Andrew Santulli ◽

...

Keyword(s):

Monoclonal Antibody ◽

Viral Load ◽

Half Life ◽

Time Course ◽

Pbpk Model ◽

Growth Suppression ◽

Dose Selection ◽

Independent Contractor ◽

Viral Growth

Abstract Background ADG20 is a fully human IgG1 monoclonal antibody engineered to have potent and broad neutralization against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other SARS-like CoVs with pandemic potential and an extended half-life. ADG20 is administered intramuscularly (IM). A QSP/PBPK model was constructed to support dose selection for a Phase 2/3 trial of ambulatory patients with mild to moderate COVID-19 (STAMP: NCT04805671). Methods A QSP/PBPK model was used to simulate receptor occupancy (RO) and drug exposure in the upper airway (nasopharyngeal/oropharyngeal epithelial lining fluid [ELF] compartment). RO was linked to an existing viral dynamic model to enable the prediction of the natural time course of viral load and the effect of ADG20 on viral clearance and infectivity rate. RO was calculated using: 1) in vitro ADG20–SARS-CoV-2 binding kinetics (association rate constant (kon) of 1.52E+06 M-1•s1 and dissociation rate constant (koff) of 2.81E-04 s-1 from a Biacore assay; 2) time course of ADG20 concentrations in ELF; and 3) time course of viral load following ADG20 administration. Molar SARS-CoV-2 viral binding site capacity was calculated assuming 40 spike proteins per virion, 3 binding sites per spike, and an initial viral load of log 107 copies/mL for all patients. The QSP/PBPK model and a 2018 CDC reference body weight distribution (45–150 kg) were used to simulate 1000 concentration-time profiles for a range of candidate ADG20 regimens. ADG20 regimens were evaluated against 2 criteria: 1) ability to attain near complete ( >90%), and durable (28-day) SARS-CoV-2 RO in the ELF; and 2) ability to maintain ELF ADG20 concentrations relative to a concentration (0.5 mg/L) associated with 100% viral growth suppression in an in vitro post-infection assay. Results A single 300 mg IM ADG20 dose met the dose selection criteria in terms of RO (Figure A) and viral growth suppression (Figure B). Conclusion These data support the evaluation of an ADG20 300 mg IM dose for the treatment of mild to moderate COVID-19. ADG20 is forecasted to attain near complete ( >90%) SARS-CoV-2 RO in the ELF and maintain ELF ADG20 concentrations above that associated with 100% viral growth suppression in vitro. Figure. QSP/PBPK model forecast of ADG20 300 mg IM in adults (A) Predicted RO expressed as percent occupancy with the dotted line representing the threshold for 90% RO. (B) Predicted median concentration of ADG20 relative to a concentration (0.5 mg/L) associated with 100% viral growth suppression as indicated by the dotted line; the shaded area represents the 90% prediction interval. Disclosures Evan D. Tarbell, PhD, Adagio Therapeutics, Inc. (Independent Contractor) Scott A. Van Wart, PhD, Adagio Therapeutics, Inc. (Independent Contractor) Laura M. Walker, PhD, Adagio Therapeutics, Inc. (Other Financial or Material Support, Laura M. Walker is an inventor on a patent application submitted by Adagio Therapeutics, Inc., describing the engineered SARS-CoV-2 antibody.) Andrew Santulli, PhD, Adagio Therapeutics, Inc. (Independent Contractor) Lynn E. Connolly, MD, PhD, Adagio Therapeutics, Inc. (Employee) Donald E Mager, PharmD, PhD, Adagio Therapeutics, Inc. (Independent Contractor) Paul G. Ambrose, PharmD, Adagio Therapeutics, Inc. (Employee)

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Light-dependent hydration of the space surrounding photoreceptors in the cat retina

Visual Neuroscience ◽

10.1017/s0952523800003047 ◽

1994 ◽

Vol 11 (4) ◽

pp. 743-752 ◽

Cited By ~ 38

Author(s):

Jian-Dong Li ◽

Victor I. Govardovskii ◽

Roy H. Steinberg

Keyword(s):

Mathematical Model ◽

Time Course ◽

Distal Portion ◽

Subretinal Space ◽

Volume Increase ◽

Physiological Event ◽

Cat Retina ◽

Interphotoreceptor Matrix ◽

Space Marker

AbstractWe have studied the effect of retinal illumination on the concentration of the extracellular space marker tetramethylammonium (TMA+) in the dark-adapted cat retina using double-barreled ion-selective microelectrodes. The retina was loaded with TMA+ by a single intravitreal injection. Retinal illumination produced a slow decrease in , which was maximal in amplitude in the most distal portion of the space surrounding photoreceptors, the subretinal space. The light-evoked decrease in was considerably slower and of a different overall time course than the light-evoked decrease in , also recorded in the subretinal space. decreased to a peak at 38 s after the onset of illumination, then slowly recovered towards the baseline, and transiently increased following the offset of illumination. It resembled the light-evoked decreases previously recorded in the in vitro preparations of frog (Huang & Karwoski, 1990, 1992) and chick (Li et al., 1992, 1994) but was considerably larger in amplitude, 22% compared with 7%. As in frog, where it was first recorded, the light-evoked decrease is considered to originate from a light-evoked increase in the volume of the subretinal space (or subretinal hydration). A mathematical model accounting for diffusion predicted that the volume increase underlying the response was 63% on average and could be as large as 95% and last for minutes. The estimated volume increase was then used to examine its effect on K+ concentration in the subretinal space. We conclude that a light-dependent hydration of the subretinal space represents a significant physiological event in the intact cat eye, which should affect the organization of the interphotoreceptor matrix, and the concentrations of all ions and metabolites located in the subretinal space.

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Glucocorticoids regulate NHE-3 transcription in OKP cells

AJP Renal Physiology ◽

10.1152/ajprenal.1996.270.1.f164 ◽

1996 ◽

Vol 270 (1) ◽

pp. F164-F169 ◽

Cited By ~ 10

Author(s):

M. Baum ◽

M. Amemiya ◽

V. Dwarakanath ◽

R. J. Alpern ◽

O. W. Moe

Keyword(s):

Gene Transcription ◽

Half Life ◽

Time Course ◽

In Vitro Transcription ◽

Mrna Abundance ◽

Proton Secretion ◽

Threefold Increase ◽

Mrna Half Life ◽

Synthetic Glucocorticoid

OKP cells express NHE-3, an amiloride-resistant Na+/H+ antiporter, which is likely an isoform responsible for apical proton secretion by the proximal tubule. We have previously shown that an amiloride-resistant Na+/H+ antiporter in OKP cells is regulated by dexamethasone, a synthetic glucocorticoid. The purpose of the present study was to examine the mechanism for the glucocorticoid-mediated increase in Na+/H+ antiporter activity. Incubation of OKP cells with 10(-6) M dexamethasone resulted in a two- to threefold increase in NHE-3 mRNA abundance. This increase was seen after 4 h of incubation with dexamethasone, a time course similar to that found for Na+/H+ antiporter activity. To examine the mechanism for the increase in NHE-3 mRNA abundance, mRNA half-life and in vitro transcription experiments were performed. NHE-3 mRNA had a half-life of 8 h in control and dexamethasone-treated cells. The rate of in vitro transcription was 1.8-fold greater when OKP cells were treated with dexamethasone. These data suggest that the glucocorticoid-mediated increase in Na+/H+ antiporter activity is due to an increase in NHE-3 gene transcription.

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A comparison of the suitability of different models for describing the gas production kinetics of whole-crop wheat

BSAP Occasional Publication ◽

10.1017/s0263967x0003264x ◽

1998 ◽

Vol 22 ◽

pp. 215-216

Author(s):

A. T. Adesogan ◽

E. Owen ◽

D. I. Givens

Keyword(s):

Mathematical Model ◽

Time Course ◽

Rumen Fluid ◽

Gas Production ◽

Ruminal Fermentation ◽

Production Kinetics ◽

Fermentation Profile ◽

Kinetics Of

Menkeet al. (1979), Beuvinket al. (1992) and Theodorouet al. (1994) developed techniques for measuring the time course of gas production of foods fermentedin vitrowith rumen fluid. These techniques require description of the fermentation profile with an appropriate mathematical model. Although several authors have used these techniques to study the ruminal fermentation of foods, little information is available on the suitability of the model chosen for describing the fermentation profile of the food under study. In this study, the models of Ørskov and McDonald (1979), Franceet al. (1993) and Beuvink and Kogut (1993) were fitted to thein vitrogas production profiles of 10 whole-crop wheat (WCW) forages (cv.Slepjner) to determine the model most suited to describing the data.

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A MATHEMATICAL MODEL FOR HUMAN AND ANIMAL LEPTOSPIROSIS

Journal of Biological System ◽

10.1142/s0218339015400057 ◽

2015 ◽

Vol 23 (supp01) ◽

pp. S55-S65 ◽

Cited By ~ 4

Author(s):

DAVID BACA-CARRASCO ◽

DANIEL OLMOS ◽

IGNACIO BARRADAS

Keyword(s):

Mathematical Model ◽

Original Model ◽

Basic Reproductive Number ◽

Reproductive Number ◽

Si Model

In this paper, we propose a SI model for the study of human and animal leptospirosis. Unlike other models for leptospirosis which consider only rodents as infection vectors, we consider that humans can be infected not only through contact with rodents, but also through any other animal that serves as a reservoir for the bacteria, and through contact with bacteria that are free in the environment. We calculate the basic reproductive number for this model, which is given in terms of the basic reproductive numbers of simpler subsystems of the original model, and propose some intervention techniques for controlling the disease based on our results.

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A mathematical model of COVID-19 transmission between frontliners and the general public

10.1101/2020.03.27.20045195 ◽

2020 ◽

Cited By ~ 1

Author(s):

Christian Alvin H. Buhat ◽

Monica C. Torres ◽

Yancee H. Olave ◽

Maica Krizna A. Gavina ◽

Edd Francis O. Felix ◽

...

Keyword(s):

Mathematical Model ◽

Customer Service ◽

General Public ◽

Food Service ◽

The Philippines ◽

Basic Reproductive Number ◽

Reproductive Number ◽

Primary Case ◽

Epidemic Curve ◽

Community Effort

ABSTRACTThe number of COVID-19 cases is continuously increasing in different countries (as of March 2020) including the Philippines. It is estimated that the basic reproductive number of COVID-19 is around 1.5 to 4. The basic reproductive number characterizes the average number of persons that a primary case can directly infect in a population full of susceptible individuals. However, there can be superspreaders that can infect more than this estimated basic reproductive number. In this study, we formulate a conceptual mathematical model on the transmission dynamics of COVID-19 between the frontliners and the general public. We assume that the general public has a reproductive number between 1.5 to 4, and frontliners (e.g. healthcare workers, customer service and retail personnel, food service crews, and transport or delivery workers) have a higher reproduction number. Our simulations show that both the frontliners and the general public should be protected or resilient against the disease. Protecting only the frontliners will not result in flattening the epidemic curve. Protecting only the general public may flatten the epidemic curve but the infection risk faced by the frontliners is still high, which may eventually affect their work. Our simple model does not consider all factors involved in COVID-19 transmission in a community, but the insights from our model results remind us of the importance of community effort in controlling the transmission of the disease. All in all, the take-home message is that everyone in the community, whether a frontliner or not, should be protected or should implement preventive measures to avoid being infected.

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Correlation of in Vivo Clot Lysis with other Thrombolytic Variables Following Administration of abbokinase ®(Tissue Culture Urokinase), to Anesthetized Dogs

10.1055/s-0039-1687046 ◽

1979 ◽

Author(s):

D. Martin ◽

J. Cain ◽

J. Chmiel ◽

S.E. El Masry

Keyword(s):

Mathematical Model ◽

Tissue Culture ◽

Plasma Levels ◽

Half Life ◽

Clot Lysis ◽

Lysis Time ◽

Euglobulin Lysis Time ◽

Anesthetized Dogs

An anesthetized dog model, using an extracorporeal loop containing an autologous radioactive clot, was utilized to test the effects of various doses of ABBOKINASE® on the rate of clot lysis and on plasma levels of urokinase, plasmin, antiplasmin, plasminogen and fibrinogen. The effects of ABBOKINASE® on hematocrit, euglobulin lysis time and125 I-clot lysis, in vitro, were also determined. Correlations were sought between plasma urokinase, plasmin, antiplasmin and the rate of clot lysis. Kinetic evaluations of half-lives of urokinase and plasmin and of the rate of regeneration of antiplasmin were made. Some of the conclusions reached were: 1) plasma fibrinogen does not decrease until antiplasmin is depleted and free plasmin appears in blood. 2) plasma urokinase levels are related to the dose infused and decrease with a half-life of about 8 minutes following infusion. 3) the rate of clot lysis in the loop is proportional to the dose of ABBOKINASE® over a defined range of doses and can be fitted to a mathematical model. 4) at lower doses, clot lysis occurs in the absence of measurable free plasmin.

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Modeling cell infection via virus-producing cells rather than free infectious virus significantly improves fits ofin vitroviral kinetic data

10.1101/627968 ◽

2019 ◽

Author(s):

Veronika Bernhauerová ◽

Veronica V. Rezelj ◽

Laura I. Levi ◽

Marco Vignuzzi

Keyword(s):

Mathematical Modeling ◽

Experimental Data ◽

Viral Load ◽

Viral Replication ◽

Mathematical Models ◽

Zika Virus ◽

Time Course ◽

Replication Cycle ◽

Infected Cells

AbstractChikungunya and Zika viruses are arthropod-borne viruses that pose significant threat to public health. Experimental data show that duringin vitroinfection both viruses exhibit qualitatively distinct replication cycle kinetics. Chikungunya viral load rapidly accumulates within the first several hours post infection whereas Zika virus begins to increase at much later times. We sought to characterize these qualitatively distinctin vitrokinetics of chikungunya and Zika viruses by fitting a family of mathematical models to time course viral load datasets. We demonstrate that the standard viral kinetic model, which considers that new infections result only from free virus penetrating susceptible cells, does not fit experimental data as well as a model in which the number of virus-infected cells is the primary determinant of infection rate. We provide biologically meaningful quantifications of the main viral kinetic parameters and show that our results support cell-to-cell or localized transmission as a significant contributor to viral infection with chikungunya and Zika viruses.ImportanceMathematical modeling has become a useful tool to tease out information about virus-host interactions and thus complements experimental work in characterizing and quantifying processes within viral replication cycle. Importantly, mathematical models can fill in incomplete data sets and identify key parameters of infection, provided the appropriate model is used. Thein vitrotime course dynamics of mosquito transmitted viruses, such as chikungunya and Zika, have not been studied by mathematical modeling and thus limits our knowledge about quantitative description of the individual determinants of viral replication cycle. This study employs dynamical modeling framework to show that the rate at which cells become virus-infected is proportional to the number or virus-infected cells rather than free extracellular virus in the milieu, a widely accepted assumption in models of viral infections. Using the refined mathematical model in combination with viral load data, we provide quantification of the main drivers of chikungunya and Zikain vitrokinetics. Together, our results bring quantitative understanding of the basic components of chikungunya and Zika virus dynamics.

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