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Expansion and Exhaustion of T-Cell Responses during Mutational Escape from Long-Term Viral Control in Two DNA/Modified Vaccinia Virus Ankara-Vaccinated and Simian-Human Immunodeficiency Virus SHIV-89.6P-Challenged Macaques

Shanmugalakshmi Sadagopal,^2, Rama Rao Amara,^1,2 Sunil Kannanganat,¹ Sunita Sharma,^2, Lakshmi Chennareddi,² and Harriet L. Robinson^1,2,3*

Emory Vaccine Center, Emory University School of Medicine, 954 Gatewood Road, Atlanta, Georgia 30329,¹ Yerkes National Primate Research Center, 954 Gatewood Road, Atlanta, Georgia 30329,² Department of Microbiology and Immunology of Emory University School of Medicine, Emory University, Atlanta, Georgia 30322³

Received 16 October 2007/ Accepted 22 January 2008

In this study, we monitored the temporal breadths, frequencies, and functions of antiviral CD4 and CD8 T cells in 2 of 22 DNA/modified vaccinia virus Ankara-vaccinated macaques that lost control of a simian-human immunodeficiency virus 89.6P challenge by 196 weeks postchallenge. Our results show that both mutation and exhaustion contributed to escape. With the reappearance of viremia, responding CD8 and CD4 T cells underwent an initial increase and then loss of breadth and frequency. Antiviral gamma interferon (IFN-)- and interleukin 2-coproducing cells were lost before IFN--producing cells and CD4 cells before CD8 cells. At euthanasia, all CD8, but no CD4, Gag epitopes detected during long-term control contained mutations.

Published ahead of print on 30 January 2008.

Present address: Infectious Disease, Vanderbilt School of Medicine, 1161 21st Avenue, A 2200 MCN, Nashville, TN 37232.

Present address: DHHS/CDC/CCID/NCHHSTP/DHPSE/LB, 1600 Clifton Road, Mailstop G45, Atlanta, GA 30329-4018.