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. 2007 Nov;81(21):11982-91.
doi: 10.1128/JVI.00946-07. Epub 2007 Aug 15.

Estimating the effectiveness of simian immunodeficiency virus-specific CD8+ T cells from the dynamics of viral immune escape

Judith N Mandl  1 , Roland R Regoes, David A Garber, Mark B Feinberg
Affiliations

Estimating the effectiveness of simian immunodeficiency virus-specific CD8+ T cells from the dynamics of viral immune escape

Judith N Mandl et al. J Virol. 2007 Nov.

Abstract

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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Figures

FIG. 1.
FIG. 1.
Schematic representation of the model used to describe the within-host dynamics of viral epitope escape due to selection pressure by specific CTLs. The four variables modeled explicitly (red circles) are wild-type virus, W, epitope escape mutants, M, cells infected with wild-type virus, IW, and cells infected with mutant virus, IM. The target cell, T(t), and effector cell, E(t), functions (green squares) are taken from the data and hence vary between animals.
FIG. 2.
FIG. 2.
Changes in the proportions of viral escape mutants (A), Ki67+ CD4+ T cells (per microliter) (B), and Tat SL8-specific CTLs (per microliter) p.i. (C) measured in the blood for control and CS blockade animals. The images shown in panels B and C have been published previously (19).
FIG. 3.
FIG. 3.
Simulation of viral escape mutant frequency using (A) different values of κ with no differences in replication rates (γ = 1) between wild-type and mutant viruses or (B) different values of γ with κ = 0.016 μl cell−1 day−1 (solid lines) and with κ = 0.032 μl cell−1 day−1 (dashed lines). Target and effector cell data used were from control animal RBm6.
FIG. 4.
FIG. 4.
Model fits to the frequency of Tat SL8 escape mutants in (A) control animals, for which κ = 0.0161 μl cell−1 day−1 (95% CI, 0.005 to 0.0197 μl cell−1 day−1), and (B) CS blockade animals, for which κ = 0.0145 μl cell−1 day−1 (95% CI, 0.0107 to 0.0176 μl cell−1 day−1).
See this image and copyright information in PMC

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