The Effects of Different HIV Type 1 Strains on Human Thymic Function

Studies of HIV-1-infected humans indicate that the thymus can be infected by HIV-1. In some of these patients, there is a significant CD4+ T cell decline and a faster disease progression. This phenomenon is more evident in pediatric patients who depend heavily on their thymus for generation of new T cells. We hypothesize that HIV-1 causes T cell regenerative failure within the thymus, which has a profound impact on disease progression. Building on our established human thymopoiesis model, we include dynamic interactions between different HIV-1 strains (R5 and X4) and thymocytes. Our results predict that thymic infection with different HIV-1 strains induces thymic dysfunction to varying degrees, contributing to differences in disease progression as observed in both HIV-1-infected children and adults. Thymic infection in children is more severe than in adults, particularly during X4 infection. This outcome is likely due to both a higher viral load and a more active thymus in pediatric patients. Our results also indicate that a viral strain switch from R5 to X4 induces further deterioration in thymopoiesis. We predict that both viral and host factors play key roles in controlling thymic infection, including strain virulence and health status of the thymus.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/63198/1/088922202320886280.pd

A multifaceted approach to modeling the immune response in tuberculosis

Tuberculosis (TB) is a deadly infectious disease caused by Mycobacterium tuberculosis (Mtb). No available vaccine is reliable and, although treatment exists, approximately 2 million people still die each year. The hallmark of TB infection is the granuloma, a self‐organizing structure of immune cells forming in the lung and lymph nodes in response to bacterial invasion. Protective immune mechanisms play a role in granuloma formation and maintenance; these act over different time/length scales (e.g., molecular, cellular, and tissue scales). The significance of specific immune factors in determining disease outcome is still poorly understood, despite incredible efforts to establish several animal systems to track infection progression and granuloma formation. Mathematical and computational modeling approaches have recently been applied to address open questions regarding host–pathogen interaction dynamics, including the immune response to Mtb infection and TB granuloma formation. This provides a unique opportunity to identify factors that are crucial to a successful outcome of infection in humans. These modeling tools not only offer an additional avenue for exploring immune dynamics at multiple biological scales but also complement and extend knowledge gained via experimental tools. We review recent modeling efforts in capturing the immune response to Mtb, emphasizing the importance of a multiorgan and multiscale approach that has tuneable resolution. Together with experimentation, systems biology has begun to unravel key factors driving granuloma formation and protective immune response in TB. WIREs Syst Biol Med 2011 3 479–489 DOI: 10.1002/wsbm.131 For further resources related to this article, please visit the WIREs websitePeer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/86857/1/131_ftp.pd

In silico evaluation and exploration of antibiotic tuberculosis treatment regimens

Abstract Background Improvement in tuberculosis treatment regimens requires selection of antibiotics and dosing schedules from a large design space of possibilities. Incomplete knowledge of antibiotic and host immune dynamics in tuberculosis granulomas impacts clinical trial design and success, and variations among clinical trials hamper side-by-side comparison of regimens. Our objective is to systematically evaluate the efficacy of isoniazid and rifampin regimens, and identify modifications to these antibiotics that improve treatment outcomes. Results We pair a spatio-temporal computational model of host immunity with pharmacokinetic and pharmacodynamic data on isoniazid and rifampin. The model is calibrated to plasma pharmacokinetic and granuloma bacterial load data from non-human primate models of tuberculosis and to tissue and granuloma measurements of isoniazid and rifampin in rabbit granulomas. We predict the efficacy of regimens containing different doses and frequencies of isoniazid and rifampin. We predict impacts of pharmacokinetic/pharmacodynamic modifications on antibiotic efficacy. We demonstrate that suboptimal antibiotic concentrations within granulomas lead to poor performance of intermittent regimens compared to daily regimens. Improvements from dose and frequency changes are limited by inherent antibiotic properties, and we propose that changes in intracellular accumulation ratios and antimicrobial activity would lead to the most significant improvements in treatment outcomes. Results suggest that an increased risk of drug resistance in fully intermittent as compared to daily regimens arises from higher bacterial population levels early during treatment. Conclusions Our systems pharmacology approach complements efforts to accelerate tuberculosis therapeutic development.http://deepblue.lib.umich.edu/bitstream/2027.42/116019/1/12918_2015_Article_221.pd

Differences in reactivation of tuberculosis induced from anti-tnf treatments are based on bioavailability in granulomatous tissue

The immune response to Mycobacterium tuberculosis (Mtb) infection is complex. Experimental evidence has revealed that tumor necrosis factor (TNF) plays a major role in host defense against Mtb in both active and latent phases of infection. TNF-neutralizing drugs used to treat inflammatory disorders have been reported to increase the risk of tuberculosis (TB), in accordance with animal studies. The present study takes a computational approach toward characterizing the role of TNF in protection against the tubercle bacillus in both active and latent infection. We extend our previous mathematical models to investigate the roles and production of soluble (sTNF) and transmembrane TNF (tmTNF). We analyze effects of anti-TNF therapy in virtual clinical trials (VCTs) by simulating two of the most commonly used therapies, anti-TNF antibody and TNF receptor fusion, predicting mechanisms that explain observed differences in TB reactivation rates. The major findings from this study are that bioavailability of TNF following anti-TNF therapy is the primary factor for causing reactivation of latent infection and that sTNF-even at very low levels-is essential for control of infection. Using a mathematical model, it is possible to distinguish mechanisms of action of the anti-TNF treatments and gain insights into the role of TNF in TB control and pathology. Our study suggests that a TNF-modulating agent could be developed that could balance the requirement for reduction of inflammation with the necessity to maintain resistance to infection and microbial diseases. Alternatively, the dose and timing of anti-TNF therapy could be modified. Anti-TNF therapy will likely lead to numerous incidents of primary TB if used in areas where exposure is likely. © 2007 Marino et al

Model of HIV-1 Disease Progression Based on Virus-Induced Lymph Node Homing and Homing-Induced Apoptosis of CD4+ Lymphocytes

Several proposed theories have described the progression of HIV infection. Even so, no concrete evidence supports any as comprehensive, including, for example, why the CD4+ T-cell counts fall from 1000/mm^3 of blood to roughly 100/mm^3 over an average 10-year period, whereas concomitant viral loads are relatively constant, increasing by several orders of magnitude in late-stage disease. Here, we develop and validate a theoretical model that altered lymphocyte circulation patterns between the lymph system and blood due to HIV-induced enhanced lymph-node homing and subsequent apoptosis of resting CD4+ T cells can explain many aspects of HIV-1 disease progression. These results lead to a recalculation of the CD4+ lymphocyte dynamics during highly active antiretroviral therapy, and also suggest new targets for therapy.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/83499/1/Kirschner_et_al.jaids2000.pd

Macrophage response to Mycobacteriumtuberculosis infection

The immune response to Mycobacteriumtuberculosis (Mtb) infection is the formation of multicellular lesions, or granolomas, in the lung of the individual. However, the structure of the granulomas and the spatial distribution of the immune cells within is not well understood. In this paper we develop a mathematical model investigating the early and initial immune response to Mtb. The model consists of coupled reaction-diffusion-advection partial differential equations governing the dynamics of the relevant macrophage and bacteria populations and a bacteria-produced chemokine. Our novel application of mathematical concepts of internal states and internal velocity allows us to begin to study this unique immunological structure. Volume changes resulting from proliferation and death terms generate a velocity field by which all cells are transported within the forming granuloma. We present numerical results for two distinct infection outcomes: controlled and uncontrolled granuloma growth. Using a simplified model we are able to analytically determine conditions under which the bacteria population decreases, representing early clearance of infection, or grows, representing the initial stages of granuloma formation.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46950/1/285_2004_Article_232.pd

Mathematical analysis of the global dynamics of a model for HTLV-I infection and ATL progression

Mathematical analysis is carried out that completely determines the global dynamics of a mathematical model for the transmission of human T-cell lymphotropic virus I (HTLV-I) infection and the development of adult T-cell leukemia (ATL). HTLV-I infection of healthy CD4+ T cells takes place through cell-to-cell contact with infected T cells. The infected T cells can remain latent and harbor virus for several years before virus production occurs. Actively infected T cells can infect other T cells and can convert to ATL cells, whose growth is assumed to follow a classical logistic growth function. Our analysis establishes that the global dynamics of T cells are completely determined by a basic reproduction number R0. If R0 1, HTLV-I infection becomes chronic, and a unique endemic equilibrium is globally stable in the interior of the feasible region. We also show that the equilibrium level of ATL-cell proliferation is higher when the HTLV-I infection of T cells is chronic than when it is acute.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/83423/1/wang2002.pd

Dose finding for new vaccines: The role for immunostimulation/immunodynamic modelling.

Current methods to optimize vaccine dose are purely empirically based, whereas in the drug development field, dosing determinations use far more advanced quantitative methodology to accelerate decision-making. Applying these established methods in the field of vaccine development may reduce the currently large clinical trial sample sizes, long time frames, high costs, and ultimately have a better potential to save lives. We propose the field of immunostimulation/immunodynamic (IS/ID) modelling, which aims to translate mathematical frameworks used for drug dosing towards optimizing vaccine dose decision-making. Analogous to Pharmacokinetic/Pharmacodynamic (PK/PD) modelling, the mathematical description of drug distribution (PK) and effect (PD) in host, IS/ID modelling approaches apply mathematical models to describe the underlying mechanisms by which the immune response is stimulated by vaccination (IS) and the resulting measured immune response dynamics (ID). To move IS/ID modelling forward, existing datasets and further data on vaccine allometry and dose-dependent dynamics need to be generated and collate, requiring a collaborative environment with input from academia, industry, regulators, governmental and non-governmental agencies to share modelling expertise, and connect modellers to vaccine data

Live attenuated HIV vaccines: Predicting the tradeoff between efficacy and safety

The utility of live attenuated vaccines for controlling HIV epidemics is being debated. Live attenuated HIV vaccines (LAHVs) could be extremely effective in protecting against infection with wild-type strains, but may not be completely safe as the attenuated strain could cause AIDS in some vaccinated individuals. We present a theoretical framework for evaluating the consequences of the tradeoff between vaccine efficacy (in terms of preventing new infections with wild-type strains) and safety (in terms of vaccine- induced AIDS deaths). We use our framework to predict, for Zimbabwe and Thailand, the epidemiological impact of 1,000 different (specified by efficacy and safety characteristics) LAHVs. We predict that paradoxically: (i) in Zimbabwe (where transmission is high) LAHVs would significantly decrease the AIDS death rate, but (ii) in Thailand (where transmission is low) exactly the same vaccines (in terms of efficacy and safety characteristics) would increase the AIDS death rate. Our results imply that a threshold transmission rate exists that determines whether any given LAHV has a beneficial or a detrimental impact. We also determine the vaccine perversity point, which is defined in terms of the fraction of vaccinated individuals who progress to AIDS as a result of the vaccine strain. Vaccination with any LAHV that causes more than 5% of vaccinated individuals to progress to AIDS in 25 years would, even 50 years later, lead to perversity (i.e., increase the annual AIDS death rate) in Thailand; these same vaccines would lead to decreases in the annual AIDS death rate in Zimbabwe.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/83498/1/PNAS-sb.pd