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Journal of Virology, June 2007, p. 5819-5828, Vol. 81, No. 11
0022-538X/07/$08.00+0     doi:10.1128/JVI.00024-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Elevated Expression Levels of Inhibitory Receptor Programmed Death 1 on Simian Immunodeficiency Virus-Specific CD8 T Cells during Chronic Infection but Not after Vaccination{triangledown}

Vijayakumar Velu,1 Sunil Kannanganat,1 Chris Ibegbu,1 Lakshmi Chennareddi,1 Francois Villinger,2 Gordon J. Freeman,3 Rafi Ahmed,1 and Rama Rao Amara1*

Vaccine Research Center, Department of Microbiology and Immunology, Yerkes National Primate Research Center,1 Department of Pathology, Emory University, Atlanta, Georgia 30329,2 Department of Medical Oncology, Dana-Farber Cancer Institute, and Department of Medicine, Harvard Medical School, Boston, Massachusetts 021153

Received 4 January 2007/ Accepted 15 March 2007

Here, we study the temporal expression of the inhibitory receptor programmed death 1 (PD-1) on simian immunodeficiency virus (SIV) Gag-specific T cells following pathogenic SIV infection or following vaccination with a DNA/modified vaccinia virus Ankara (DNA/MVA) vaccine and simian/human immunodeficiency virus (SHIV) challenge in macaques. Following infection, the majority (>95%) of Gag-specific CD8 T cells expressed PD-1, and the level of PD-1 expression per cell increased over time. The level of PD-1 expression in lymph nodes and rectal mucosal tissue, the major sites of virus replication, was higher compared to blood. In vitro blockade of PD-1 resulted in enhanced proliferation of SIV-specific CD8 as well as CD4 T cells. In contrast, following vaccination, the majority of peak effector Gag-specific CD8 T cells expressed low levels of PD-1, and these levels decreased further as the cells differentiated into memory cells. In addition, following SHIV challenge of these vaccinated macaques, the level of PD-1 expression on Gag-specific CD8 T cells correlated positively with plasma viremia. These results demonstrate that SIV-specific CD8 T cells express PD-1 after exposure to antigen but downregulate expression under conditions of antigen clearance and enhance expression under conditions of antigen persistence. They also demonstrate that the level of PD-1 expression per cell rather than the presence or absence of expression plays an important role in regulating CD8 T-cell dysfunction in pathogenic SIV infection. In addition, they demonstrate that similar to HIV infection, the PD-1:PD-1 ligand inhibitory pathway is operational in pathogenic SIV infection, and the macaque/SIV model would be ideal to test the safety and therapeutic benefit of blocking this pathway in vivo.

* Corresponding author. Mailing address: 954 Gatewood Road NE, Atlanta, GA 30329. Phone: (404) 727-8765. Fax: (404) 727-7768. E-mail: rama{at}rmy.emory.edu

{triangledown} Published ahead of print on 21 March 2007.

Journal of Virology, June 2007, p. 5819-5828, Vol. 81, No. 11
0022-538X/07/$08.00+0     doi:10.1128/JVI.00024-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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