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Journal of Virology, November 2007, p. 11982-11991, Vol. 81, No. 21
0022-538X/07/$08.00+0     doi:10.1128/JVI.00946-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

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

Judith N. Mandl,1,3,{dagger} Roland R. Regoes,2,{dagger},{ddagger} David A. Garber,3 and Mark B. Feinberg3*

Graduate Program in Population Biology, Ecology, and Evolution, Emory University, 954 Gatewood Road, Atlanta, Georgia 30329,1 Department of Biology, Emory University, Atlanta, Georgia,2 Emory Vaccine Center, Emory University School of Medicine, 954 Gatewood Road, Atlanta, Georgia 303293

Received 2 May 2007/ Accepted 6 August 2007

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.

* Corresponding author. Present address: Merck Vaccine Division, WP97-A337, 770 Sumneytown Pike, P.O. Box 4, West Point, PA 19486. Phone: (215) 652-8664. Fax: (215) 652-8918. E-mail: mark_feinberg{at}merck.com

{triangledown} Published ahead of print on 15 August 2007.

{dagger} These authors contributed equally to this work.

{ddagger} Present address: Theoretical Biology, ETH Zurich, Universitaetsstr. 16, ETH Zentrum, CHN H76.1, CH-8092 Zurich, Switzerland.

Journal of Virology, November 2007, p. 11982-11991, Vol. 81, No. 21
0022-538X/07/$08.00+0     doi:10.1128/JVI.00946-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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