A new paper from Rama Rao Amara's group at Emory University offers the first detailed look at PD-1 expression on T cells in SIV-infected macaques. The study jibes with those previously published in mice and humans, but also adds the potentially important finding that SIV-specific memory T cell responses induced by vaccination appear less susceptible to exhaustion than the SIV-specific T cell responses that develop in naive animals. The authors also note that their results suggest that the SIV/macaque model will be useful for evaluating the potential risks and benefits of blocking PD-1/PD-1 ligand interactions; in mice, this strategy has been shown to revive exhausted T cell responses, but it is also known to carry a risk of triggering autoimmunity.
JVI Accepts, published online ahead of print on 21 March 2007
J. Virol. doi:10.1128/JVI.00024-07
Vijayakumar Velu, Sunil Kannanganat, Chris Ibegbu, Lakshmi Chennareddi, Francois Villinger, Gordon J. Freeman, Rafi Ahmed, and Rama Rao Amara
Vaccine Research Center, Department of Microbiology and Immunology, Yerkes National Primate Research Center, and Department of Pathology, Emory University, Atlanta, GA, 30329, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA
Abstract
Here, we study the temporal expression of the inhibitory receptor programmed death-1 (PD-1) on SIV Gag-specific T cells following pathogenic SIV infection, or following vaccination with a DNA/MVA vaccine and 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. 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 following exposure to antigen but down regulate 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.
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