Data from human clinical trials have shown that the hepatitis B virus (HBV) follows complex profi... more Data from human clinical trials have shown that the hepatitis B virus (HBV) follows complex profiles, such as bi-phasic, tri-phasic, stepwise decay and rebound. We utilized a deterministic model of HBV kinetics following antiviral therapy to uncover the mechanistic interactions behind HBV dynamics. Analytical investigation of the model was used to separate the parameter space describing virus decay and rebound. Monte Carlo sampling of the parameter space was used to determine the virological, pharmacological and immunological factors that separate the bi-phasic and tri-phasic virus profiles. We found that the level of liver infection at the start of therapy best separates the decay patterns. Moreover, drug efficacy, ratio between division of uninfected and infected cells, and the strength of cytotoxic immune response are important in assessing the amount of liver damage experienced over time and in quantifying the duration of therapy leading to virus resolution in each of the observ...
T cell populations are regulated both by signals specific to the T-cell receptor (TCR) and by sig... more T cell populations are regulated both by signals specific to the T-cell receptor (TCR) and by signals and resources, such as cytokines and space, that act independently of TCR specificity. Although it has been demonstrated that disruption of either of these pathways has a profound effect on T-cell development, we do not yet have an understanding of the dynamical interactions of these pathways in their joint shaping of the T cell repertoire. Complete DiGeorge Anomaly is a developmental abnormality that results in the failure of the thymus to develop, absence of T cells, and profound immune deficiency. After receiving thymic tissue grafts, patients suffering from DiGeorge anomaly develop T cells derived from their own precursors but matured in the donor tissue. We followed three DiGeorge patients after thymus transplantation to utilize the remarkable opportunity these subjects provide to elucidate human T-cell developmental regulation. Our goal is the determination of the respective roles of TCR-specific vs. TCR-nonspecific regulatory signals in the growth of these emerging T-cell populations. During the course of the study, we measured peripheral blood T-cell concentrations, TCRb V gene-segment usage and CDR3length spectratypes over two years or more for each of the subjects. We find, through statistical analysis based on a novel stochastic population-dynamic T-cell model, that the carrying capacity corresponding to TCR-specific resources is approximately 1000-fold larger than that of TCR-nonspecific resources, implying that the size of the peripheral T-cell pool at steady state is determined almost entirely by TCR-nonspecific mechanisms. Nevertheless, the diversity of the TCR repertoire depends crucially on TCR-specific regulation. The estimated strength of this TCR-specific regulation is sufficient to ensure rapid establishment of TCR repertoire diversity in the early phase of T cell population growth, and to maintain TCR repertoire diversity in the face of substantial clonal expansion-induced perturbation from the steady state.
Background: T-cell receptor diversity correlates with immune competency and is of particular inte... more Background: T-cell receptor diversity correlates with immune competency and is of particular interest in patients undergoing immune reconstitution. Spectratyping generates data about T-cell receptor CDR3 length distribution for each BV gene but is technically complex. Flow cytometry can also be used to generate data about T-cell receptor BV gene usage, but its utility has not been compared to or tested in combination with spectratyping. Results: Using flow cytometry and spectratype data, we have defined a divergence metric that quantifies the deviation from normal of T-cell receptor repertoire. We have shown that the sample size is a sensitive parameter in the predicted flow divergence values, but not in the spectratype divergence values. We have derived two ways to correct for the measurement bias using mathematical and statistical approaches and have predicted a lower bound in the number of lymphocytes needed when using the divergence as a substitute for diversity. Conclusions: Using both flow cytometry and spectratyping of T-cells, we have defined the divergence measure as an indirect measure of T-cell receptor diversity. We have shown the dependence of the divergence measure on the sample size before it can be used to make predictions regarding the diversity of the T-cell receptor repertoire.
Proceedings of the Royal Society B: Biological Sciences, 2021
The relationship between the inoculum dose and the ability of the pathogen to invade the host is ... more The relationship between the inoculum dose and the ability of the pathogen to invade the host is poorly understood. Experimental studies in non-human primates infected with different inoculum doses of hepatitis B virus have shown a non-monotonic relationship between dose magnitude and infection outcome, with high and low doses leading to 100% liver infection and intermediate doses leading to less than 0.1% liver infection, corresponding to CD4 T-cell priming. Since hepatitis B clearance is CD8 T-cell mediated, the question of whether the inoculum dose influences CD8 T-cell dynamics arises. To help answer this question, we developed a mathematical model of virus–host interaction following hepatitis B virus infection. Our model explains the experimental data well, and predicts that the inoculum dose affects both the timing of the CD8 T-cell expansion and the quality of its response, especially the non-cytotoxic function. We find that a low-dose challenge leads to slow CD8 T-cell expan...
Hepatitis B is a DNA virus that infects liver cells and can cause both acute and chronic disease.... more Hepatitis B is a DNA virus that infects liver cells and can cause both acute and chronic disease. It is believed that both viral and host factors are responsible for determining whether the infection is cleared or becomes chronic. Here we investigate the mechanism of protection by developing a mathematical model of the antibody response following hepatitis B virus (HBV) infection. We fitted the model to data from seven infected adults identified during acute infection and determined the ability of the virus to escape neutralization through overproduction of non-infectious subviral particles, which have HBs proteins on their surface, but do not contain nucleocapsid protein and viral nucleic acids. We showed that viral clearance can be achieved for high anti-HBV antibody levels, as in vaccinated individuals, when: (1) the rate of synthesis of hepatitis B subviral particles is slow; (2) the rate of synthesis of hepatitis B subviral particles is high but either anti-HBV antibody product...
The RNA interference (RNAi) drug ARC-520 was shown to be effective in reducing serum hepatitis B ... more The RNA interference (RNAi) drug ARC-520 was shown to be effective in reducing serum hepatitis B virus (HBV) DNA, hepatitis B e antigen (HBeAg) and hepatitis B surface antigen (HBsAg) in HBeAg-positive patients treated with a single dose of ARC-520 and daily nucleosidic analogue (entecavir). To provide insights into HBV dynamics under ARC-520 treatment and its efficacy in blocking HBV DNA, HBsAg, and HBeAg production we developed a multi-compartmental pharmacokinetic–pharamacodynamic model and calibrated it with frequent measured HBV kinetic data. We showed that the time-dependent single dose ARC-520 efficacies in blocking HBsAg and HBeAg are more than 96% effective around day 1, and slowly wane to 50% in 1–4 months. The combined single dose ARC-520 and entecavir effect on HBV DNA was constant over time, with efficacy of more than 99.8%. The observed continuous HBV DNA decline is entecavir mediated, the strong but transient HBsAg and HBeAg decays are ARC-520 mediated. The modeling f...
The highly controlled migration of neutrophils toward the site of an infection can be altered whe... more The highly controlled migration of neutrophils toward the site of an infection can be altered when they are trained with lipopolysaccharides (LPS), with high dose LPS enhancing neutrophil migratory pattern toward the bacterial derived source signal and super-low dose LPS inducing either migration toward an intermediary signal or dysregulation and oscillatory movement. Empirical studies that use microfluidic chemotaxis-chip devices with two opposing chemoattractants showed differential neutrophil migration after challenge with different LPS doses. The epigenetic alterations responsible for changes in neutrophil migratory behavior are unknown. We developed two mathematical models that evaluate the mechanistic interactions responsible for neutrophil migratory decision-making when exposed to competing chemoattractants and challenged with LPS. The first model, which considers the interactions between the receptor densities of two competing chemoattractants, their kinases, and LPS, displa...
Vaccination is considered the best strategy for limiting and eliminating the COVID-19 pandemic. T... more Vaccination is considered the best strategy for limiting and eliminating the COVID-19 pandemic. The success of this strategy relies on the rate of vaccine deployment and acceptance across the globe. As these efforts are being conducted, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus is continuously mutating, which leads to the emergence of variants with increased transmissibility, virulence, and lower response the vaccines. One important question is whether surveillance testing is still needed in order to limit SARS-CoV-2 transmission in an increasingly vaccinated population. In this study, we developed a multi-scale mathematical model of SARS-CoV-2 transmission in a vaccinated population and used it to predict the role of testing in an outbreak with alpha and delta variants. We found that, when the alpha variant is dominant, testing is effective when vaccination levels are low to moderate and its impact is diminished when vaccination levels are high. When th...
The virus Hepatitis B infects liver cells, leading to either acute or chronic liver disease. Immu... more The virus Hepatitis B infects liver cells, leading to either acute or chronic liver disease. Immune responses involve both curing and killing of cells. Stability analyses show that viral clearance depends only on the strength of the combined killing and curing, independent of the characteristics of the cured cells.
T cell populations are regulated both by signals specific to the T-cell receptor (TCR) and by sig... more T cell populations are regulated both by signals specific to the T-cell receptor (TCR) and by signals and resources, such as cytokines and space, that act independently of TCR specificity. Although it has been demonstrated that disruption of either of these pathways has a profound effect on T-cell development, we do not yet have an understanding of the dynamical interactions of these pathways in their joint shaping of the T cell repertoire. Complete DiGeorge Anomaly is a developmental abnormality that results in the failure of the thymus to develop, absence of T cells, and profound immune deficiency. After receiving thymic tissue grafts, patients suffering from DiGeorge anomaly develop T cells derived from their own precursors but matured in the donor tissue. We followed three DiGeorge patients after thymus transplantation to utilize the remarkable opportunity these subjects provide to elucidate human T-cell developmental regulation. Our goal is the determination of the respective r...
Usutu virus (USUV; family: Flaviviridae, genus: Flavivirus), is an emerging zoonotic arbovirus th... more Usutu virus (USUV; family: Flaviviridae, genus: Flavivirus), is an emerging zoonotic arbovirus that causes severe neuroinvasive disease in humans and has been implicated in the loss of breeding bird populations in Europe. USUV is maintained in an enzootic cycle between ornithophilic mosquitos and wild birds. As a member of the Japanese encephalitis serocomplex, USUV is closely related to West Nile virus (WNV) and St. Louis encephalitis virus (SLEV), both neuroinvasive arboviruses endemic in wild bird populations in the United States. An avian model for USUV is essential to understanding zoonotic transmission. Here we describe the first avian models of USUV infection with the development of viremia. Juvenile commercial ISA Brown chickens were susceptible to infection by multiple USUV strains with evidence of cardiac lesions. Juvenile chickens from two chicken lines selected for high (HAS) or low (LAS) antibody production against sheep red blood cells showed markedly different respons...
Experimental studies in non-human primates inoculated with hepatitis B virus have shown that viru... more Experimental studies in non-human primates inoculated with hepatitis B virus have shown that virus dose influences the kinetics of virus spread and the disease outcome. In particular, high and low doses lead to 100% liver infection, while intermediate doses lead to less than 0.1% liver infection. To determine the relationship between virus dynamics, percentage of liver infection, and immune priming we developed an in-host mathematical model that considers the effects of cellular immune responses in controlling the disease. We fitted the model to data and predicted correlations between dose size, the timing of the immune response, the potency of immune effects, and disease outcome. Such results can guide our understanding of the virus-host dynamics that control the virus or permit a transition to chronic disease. Authors • Stanca Ciupe, Virginia Tech, U.S., [email protected] • Jonathan Forde, Hobart and William Smith Colleges, U.S., [email protected] • Naveen K. Vaidya, San Diego State Unive...
E peter Turchin and anthropologist Andrey Korotayev (2006) propose that population size and incid... more E peter Turchin and anthropologist Andrey Korotayev (2006) propose that population size and incidence of internal warfare or sociopolitical instability exhibit a deterministic relationship in prestate societies. Important to their thesis is that both population size and incidence of instability are, and must be treated as, dynamic variables: population growth eventually causes an increase in instability, with a lag, whereas increased instability, also with a lag, eventually leads to decreases in population size. Because of these lags, they argue that a straightforward attempt to cross-tabulate current incidence of warfare against current population size, as done by Keeley (1996, 117–121, 202), for example, is theoretically indefensible and, practically, likely to lead to spurious results. Indeed, Keeley’s tabulation failed to confirm a positive relationship between population size and instability in a series of societies of various scale,1 although Ember (1982) demonstrated a positi...
Data from human clinical trials have shown that the hepatitis B virus (HBV) follows complex profi... more Data from human clinical trials have shown that the hepatitis B virus (HBV) follows complex profiles, such as bi-phasic, tri-phasic, stepwise decay and rebound. We utilized a deterministic model of HBV kinetics following antiviral therapy to uncover the mechanistic interactions behind HBV dynamics. Analytical investigation of the model was used to separate the parameter space describing virus decay and rebound. Monte Carlo sampling of the parameter space was used to determine the virological, pharmacological and immunological factors that separate the bi-phasic and tri-phasic virus profiles. We found that the level of liver infection at the start of therapy best separates the decay patterns. Moreover, drug efficacy, ratio between division of uninfected and infected cells, and the strength of cytotoxic immune response are important in assessing the amount of liver damage experienced over time and in quantifying the duration of therapy leading to virus resolution in each of the observ...
T cell populations are regulated both by signals specific to the T-cell receptor (TCR) and by sig... more T cell populations are regulated both by signals specific to the T-cell receptor (TCR) and by signals and resources, such as cytokines and space, that act independently of TCR specificity. Although it has been demonstrated that disruption of either of these pathways has a profound effect on T-cell development, we do not yet have an understanding of the dynamical interactions of these pathways in their joint shaping of the T cell repertoire. Complete DiGeorge Anomaly is a developmental abnormality that results in the failure of the thymus to develop, absence of T cells, and profound immune deficiency. After receiving thymic tissue grafts, patients suffering from DiGeorge anomaly develop T cells derived from their own precursors but matured in the donor tissue. We followed three DiGeorge patients after thymus transplantation to utilize the remarkable opportunity these subjects provide to elucidate human T-cell developmental regulation. Our goal is the determination of the respective roles of TCR-specific vs. TCR-nonspecific regulatory signals in the growth of these emerging T-cell populations. During the course of the study, we measured peripheral blood T-cell concentrations, TCRb V gene-segment usage and CDR3length spectratypes over two years or more for each of the subjects. We find, through statistical analysis based on a novel stochastic population-dynamic T-cell model, that the carrying capacity corresponding to TCR-specific resources is approximately 1000-fold larger than that of TCR-nonspecific resources, implying that the size of the peripheral T-cell pool at steady state is determined almost entirely by TCR-nonspecific mechanisms. Nevertheless, the diversity of the TCR repertoire depends crucially on TCR-specific regulation. The estimated strength of this TCR-specific regulation is sufficient to ensure rapid establishment of TCR repertoire diversity in the early phase of T cell population growth, and to maintain TCR repertoire diversity in the face of substantial clonal expansion-induced perturbation from the steady state.
Background: T-cell receptor diversity correlates with immune competency and is of particular inte... more Background: T-cell receptor diversity correlates with immune competency and is of particular interest in patients undergoing immune reconstitution. Spectratyping generates data about T-cell receptor CDR3 length distribution for each BV gene but is technically complex. Flow cytometry can also be used to generate data about T-cell receptor BV gene usage, but its utility has not been compared to or tested in combination with spectratyping. Results: Using flow cytometry and spectratype data, we have defined a divergence metric that quantifies the deviation from normal of T-cell receptor repertoire. We have shown that the sample size is a sensitive parameter in the predicted flow divergence values, but not in the spectratype divergence values. We have derived two ways to correct for the measurement bias using mathematical and statistical approaches and have predicted a lower bound in the number of lymphocytes needed when using the divergence as a substitute for diversity. Conclusions: Using both flow cytometry and spectratyping of T-cells, we have defined the divergence measure as an indirect measure of T-cell receptor diversity. We have shown the dependence of the divergence measure on the sample size before it can be used to make predictions regarding the diversity of the T-cell receptor repertoire.
Proceedings of the Royal Society B: Biological Sciences, 2021
The relationship between the inoculum dose and the ability of the pathogen to invade the host is ... more The relationship between the inoculum dose and the ability of the pathogen to invade the host is poorly understood. Experimental studies in non-human primates infected with different inoculum doses of hepatitis B virus have shown a non-monotonic relationship between dose magnitude and infection outcome, with high and low doses leading to 100% liver infection and intermediate doses leading to less than 0.1% liver infection, corresponding to CD4 T-cell priming. Since hepatitis B clearance is CD8 T-cell mediated, the question of whether the inoculum dose influences CD8 T-cell dynamics arises. To help answer this question, we developed a mathematical model of virus–host interaction following hepatitis B virus infection. Our model explains the experimental data well, and predicts that the inoculum dose affects both the timing of the CD8 T-cell expansion and the quality of its response, especially the non-cytotoxic function. We find that a low-dose challenge leads to slow CD8 T-cell expan...
Hepatitis B is a DNA virus that infects liver cells and can cause both acute and chronic disease.... more Hepatitis B is a DNA virus that infects liver cells and can cause both acute and chronic disease. It is believed that both viral and host factors are responsible for determining whether the infection is cleared or becomes chronic. Here we investigate the mechanism of protection by developing a mathematical model of the antibody response following hepatitis B virus (HBV) infection. We fitted the model to data from seven infected adults identified during acute infection and determined the ability of the virus to escape neutralization through overproduction of non-infectious subviral particles, which have HBs proteins on their surface, but do not contain nucleocapsid protein and viral nucleic acids. We showed that viral clearance can be achieved for high anti-HBV antibody levels, as in vaccinated individuals, when: (1) the rate of synthesis of hepatitis B subviral particles is slow; (2) the rate of synthesis of hepatitis B subviral particles is high but either anti-HBV antibody product...
The RNA interference (RNAi) drug ARC-520 was shown to be effective in reducing serum hepatitis B ... more The RNA interference (RNAi) drug ARC-520 was shown to be effective in reducing serum hepatitis B virus (HBV) DNA, hepatitis B e antigen (HBeAg) and hepatitis B surface antigen (HBsAg) in HBeAg-positive patients treated with a single dose of ARC-520 and daily nucleosidic analogue (entecavir). To provide insights into HBV dynamics under ARC-520 treatment and its efficacy in blocking HBV DNA, HBsAg, and HBeAg production we developed a multi-compartmental pharmacokinetic–pharamacodynamic model and calibrated it with frequent measured HBV kinetic data. We showed that the time-dependent single dose ARC-520 efficacies in blocking HBsAg and HBeAg are more than 96% effective around day 1, and slowly wane to 50% in 1–4 months. The combined single dose ARC-520 and entecavir effect on HBV DNA was constant over time, with efficacy of more than 99.8%. The observed continuous HBV DNA decline is entecavir mediated, the strong but transient HBsAg and HBeAg decays are ARC-520 mediated. The modeling f...
The highly controlled migration of neutrophils toward the site of an infection can be altered whe... more The highly controlled migration of neutrophils toward the site of an infection can be altered when they are trained with lipopolysaccharides (LPS), with high dose LPS enhancing neutrophil migratory pattern toward the bacterial derived source signal and super-low dose LPS inducing either migration toward an intermediary signal or dysregulation and oscillatory movement. Empirical studies that use microfluidic chemotaxis-chip devices with two opposing chemoattractants showed differential neutrophil migration after challenge with different LPS doses. The epigenetic alterations responsible for changes in neutrophil migratory behavior are unknown. We developed two mathematical models that evaluate the mechanistic interactions responsible for neutrophil migratory decision-making when exposed to competing chemoattractants and challenged with LPS. The first model, which considers the interactions between the receptor densities of two competing chemoattractants, their kinases, and LPS, displa...
Vaccination is considered the best strategy for limiting and eliminating the COVID-19 pandemic. T... more Vaccination is considered the best strategy for limiting and eliminating the COVID-19 pandemic. The success of this strategy relies on the rate of vaccine deployment and acceptance across the globe. As these efforts are being conducted, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus is continuously mutating, which leads to the emergence of variants with increased transmissibility, virulence, and lower response the vaccines. One important question is whether surveillance testing is still needed in order to limit SARS-CoV-2 transmission in an increasingly vaccinated population. In this study, we developed a multi-scale mathematical model of SARS-CoV-2 transmission in a vaccinated population and used it to predict the role of testing in an outbreak with alpha and delta variants. We found that, when the alpha variant is dominant, testing is effective when vaccination levels are low to moderate and its impact is diminished when vaccination levels are high. When th...
The virus Hepatitis B infects liver cells, leading to either acute or chronic liver disease. Immu... more The virus Hepatitis B infects liver cells, leading to either acute or chronic liver disease. Immune responses involve both curing and killing of cells. Stability analyses show that viral clearance depends only on the strength of the combined killing and curing, independent of the characteristics of the cured cells.
T cell populations are regulated both by signals specific to the T-cell receptor (TCR) and by sig... more T cell populations are regulated both by signals specific to the T-cell receptor (TCR) and by signals and resources, such as cytokines and space, that act independently of TCR specificity. Although it has been demonstrated that disruption of either of these pathways has a profound effect on T-cell development, we do not yet have an understanding of the dynamical interactions of these pathways in their joint shaping of the T cell repertoire. Complete DiGeorge Anomaly is a developmental abnormality that results in the failure of the thymus to develop, absence of T cells, and profound immune deficiency. After receiving thymic tissue grafts, patients suffering from DiGeorge anomaly develop T cells derived from their own precursors but matured in the donor tissue. We followed three DiGeorge patients after thymus transplantation to utilize the remarkable opportunity these subjects provide to elucidate human T-cell developmental regulation. Our goal is the determination of the respective r...
Usutu virus (USUV; family: Flaviviridae, genus: Flavivirus), is an emerging zoonotic arbovirus th... more Usutu virus (USUV; family: Flaviviridae, genus: Flavivirus), is an emerging zoonotic arbovirus that causes severe neuroinvasive disease in humans and has been implicated in the loss of breeding bird populations in Europe. USUV is maintained in an enzootic cycle between ornithophilic mosquitos and wild birds. As a member of the Japanese encephalitis serocomplex, USUV is closely related to West Nile virus (WNV) and St. Louis encephalitis virus (SLEV), both neuroinvasive arboviruses endemic in wild bird populations in the United States. An avian model for USUV is essential to understanding zoonotic transmission. Here we describe the first avian models of USUV infection with the development of viremia. Juvenile commercial ISA Brown chickens were susceptible to infection by multiple USUV strains with evidence of cardiac lesions. Juvenile chickens from two chicken lines selected for high (HAS) or low (LAS) antibody production against sheep red blood cells showed markedly different respons...
Experimental studies in non-human primates inoculated with hepatitis B virus have shown that viru... more Experimental studies in non-human primates inoculated with hepatitis B virus have shown that virus dose influences the kinetics of virus spread and the disease outcome. In particular, high and low doses lead to 100% liver infection, while intermediate doses lead to less than 0.1% liver infection. To determine the relationship between virus dynamics, percentage of liver infection, and immune priming we developed an in-host mathematical model that considers the effects of cellular immune responses in controlling the disease. We fitted the model to data and predicted correlations between dose size, the timing of the immune response, the potency of immune effects, and disease outcome. Such results can guide our understanding of the virus-host dynamics that control the virus or permit a transition to chronic disease. Authors • Stanca Ciupe, Virginia Tech, U.S., [email protected] • Jonathan Forde, Hobart and William Smith Colleges, U.S., [email protected] • Naveen K. Vaidya, San Diego State Unive...
E peter Turchin and anthropologist Andrey Korotayev (2006) propose that population size and incid... more E peter Turchin and anthropologist Andrey Korotayev (2006) propose that population size and incidence of internal warfare or sociopolitical instability exhibit a deterministic relationship in prestate societies. Important to their thesis is that both population size and incidence of instability are, and must be treated as, dynamic variables: population growth eventually causes an increase in instability, with a lag, whereas increased instability, also with a lag, eventually leads to decreases in population size. Because of these lags, they argue that a straightforward attempt to cross-tabulate current incidence of warfare against current population size, as done by Keeley (1996, 117–121, 202), for example, is theoretically indefensible and, practically, likely to lead to spurious results. Indeed, Keeley’s tabulation failed to confirm a positive relationship between population size and instability in a series of societies of various scale,1 although Ember (1982) demonstrated a positi...
Uploads
Papers by Stanca Ciupe