Mathematical models of cytotoxic T‐lymphocyte killing

Regoes, Roland R.; Yates, Andrew J.; Antia, Rustom

doi:10.1038/sj.icb.7100053

Cited by 38 publications

(35 citation statements)

References 33 publications

(43 reference statements)

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“…From our model, the mean killing rate is between 0.07 and 0.22 day Ϫ1 for control animals. Interestingly, our estimate is substantially (ϳ100-fold) lower than the killing constant that was estimated for specific CD8 ϩ T cells in the lymphocytic choriomeningitis virus murine model from the decline in adoptively transferred, peptide-pulsed target cells (46), and possible reasons for this are reviewed extensively elsewhere (47).…”

Section: Discussionmentioning

confidence: 72%

Estimating the Effectiveness of Simian Immunodeficiency Virus-Specific CD8⁺T Cells from the Dynamics of Viral Immune Escape

Mandl

Regoes

Garber

et al. 2007

J Virol

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Antiviral CD8؉ T cells are thought to play a significant role in limiting the viremia of human and simian immunodeficiency virus (HIV and SIV, respectively) infections. However, it has not been possible to measure the in vivo effectiveness of cytotoxic T cells (CTLs), and hence their contribution to the death rate of CD4 ؉ T cells is unknown. Here, we estimated the ability of a prototypic antigen-specific CTL response against a well-characterized epitope to recognize and kill infected target cells by monitoring the immunodominant Mamu-A*01-restricted Tat SL8 epitope for escape from Tat-specific CTLs in SIVmac239-infected macaques. Fitting a mathematical model that incorporates the temporal kinetics of specific CTLs to the frequency of Tat SL8 escape mutants during acute SIV infection allowed us to estimate the in vivo killing rate constant per Tat SL8-specific CTL. Using this unique data set, we show that at least during acute SIV infection, certain antiviral CD8 ؉ T cells can have a significant impact on shortening the longevity of infected CD4 ؉ T cells and hence on suppressing virus replication. Unfortunately, due to viral escape from immune pressure and a dependency of the effectiveness of antiviral CD8 ؉ T-cell responses on the availability of sufficient CD4 ؉ T cells, the impressive early potency of the CTL response may wane in the transition to the chronic stage of the infection.

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Section: Discussionmentioning

confidence: 72%

Estimating the Effectiveness of Simian Immunodeficiency Virus-Specific CD8⁺T Cells from the Dynamics of Viral Immune Escape

Mandl

Regoes

Garber

et al. 2007

J Virol

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“…Others have also estimated CD8 CTL killing rates in murine LCMV infection by fitting a closed-form model to experimental data, with the estimated half-life of infected cells being about 10 min (6.9 ϫ 10 Ϫ3 days) (42,43,60). There are several factors that could explain the difference in target cell half-life between the two systems.…”

Section: Discussionmentioning

confidence: 99%

Quantifying the Early Immune Response and Adaptive Immune Response Kinetics in Mice Infected with Influenza A Virus

Miao

Hollenbaugh

Zand

et al. 2010

J Virol

202

350

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Seasonal and pandemic influenza A virus (IAV) continues to be a public health threat. However, we lack a detailed and quantitative understanding of the immune response kinetics to IAV infection and which biological parameters most strongly influence infection outcomes. To address these issues, we use modeling approaches combined with experimental data to quantitatively investigate the innate and adaptive immune responses to primary IAV infection. Mathematical models were developed to describe the dynamic interactions between target (epithelial) cells, influenza virus, cytotoxic T lymphocytes (CTLs), and virus-specific IgG and IgM. IAV and immune kinetic parameters were estimated by fitting models to a large data set obtained from primary H3N2 IAV infection of 340 mice. Prior to a detectable virus-specific immune response (before day 5), the estimated half-life of infected epithelial cells is ϳ1.2 days, and the half-life of free infectious IAV is ϳ4 h. During the adaptive immune response (after day 5), the average half-life of infected epithelial cells is ϳ0.5 days, and the average half-life of free infectious virus is ϳ1.8 min. During the adaptive phase, model fitting confirms that CD8 ؉ CTLs are crucial for limiting infected cells, while virus-specific IgM regulates free IAV levels. This may imply that CD4 T cells and class-switched IgG antibodies are more relevant for generating IAV-specific memory and preventing future infection via a more rapid secondary immune response. Also, simulation studies were performed to understand the relative contributions of biological parameters to IAV clearance. This study provides a basis to better understand and predict influenza virus immunity.

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“…Here we review these studies to see if they indeed support the minor contribution of the lytic effects of CTLs, and whether they are truly incompatible with rapid CTL killing rates. There are multiple ways to report CTL-mediated killing rates (see [10][11][12] for excellent overviews and how to interconvert these rates). In this review, we report published estimates of killing rates as the death rate of productively infected cells induced by all CTLs together.…”

Section: Introductionmentioning

confidence: 99%

What do mathematical models tell us about killing rates during HIV-1 infection?

2015

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Over the past few decades the extent to which cytotoxic T lymphocytes (CTLs) control human immunodeficiency virus (HIV) replication has been studied extensively, yet their role and mode of action remain controversial. In some studies, CTLs were found to kill a large fraction of the productively infected cells relative to the viral cytopathicity, whereas in others CTLs were suggested to kill only a small fraction of infected cells. In this review, we compile published estimates of CTL-mediated death rates, and examine whether these studies permit determining the rate at which CTLs kill HIV-1 infected cells. We highlight potential misinterpretations of the CTL-killing rates from the escape rates of mutants, and from perturbations of the steady state viral load during chronic infection. Our major conclusion is that CTL-mediated killing rates remain unknown. But contrary to current consensus, we argue that killing rates higher than one per day are perfectly consistent with the experimental data, which would imply that the majority of the productively infected cells could still die from CTL-mediated killing rather than from viral cytopathicity.

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Mathematical models of cytotoxic T‐lymphocyte killing

Cited by 38 publications

References 33 publications

Estimating the Effectiveness of Simian Immunodeficiency Virus-Specific CD8⁺T Cells from the Dynamics of Viral Immune Escape

Estimating the Effectiveness of Simian Immunodeficiency Virus-Specific CD8⁺T Cells from the Dynamics of Viral Immune Escape

Quantifying the Early Immune Response and Adaptive Immune Response Kinetics in Mice Infected with Influenza A Virus

What do mathematical models tell us about killing rates during HIV-1 infection?

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Mathematical models of cytotoxic T‐lymphocyte killing

Cited by 38 publications

References 33 publications

Estimating the Effectiveness of Simian Immunodeficiency Virus-Specific CD8+T Cells from the Dynamics of Viral Immune Escape

Estimating the Effectiveness of Simian Immunodeficiency Virus-Specific CD8+T Cells from the Dynamics of Viral Immune Escape

Quantifying the Early Immune Response and Adaptive Immune Response Kinetics in Mice Infected with Influenza A Virus

What do mathematical models tell us about killing rates during HIV-1 infection?

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Estimating the Effectiveness of Simian Immunodeficiency Virus-Specific CD8⁺T Cells from the Dynamics of Viral Immune Escape

Estimating the Effectiveness of Simian Immunodeficiency Virus-Specific CD8⁺T Cells from the Dynamics of Viral Immune Escape