Soluble PD-1 rescues the proliferative response of simian immunodeficiency virus-specific CD4 and CD8 T cells during chronic infection

• Authors: Nattawat Onlamoon, Emory University; Kenneth Rogers, Emory University; Ann E Mayne, Emory University; Kovit Pattanapanyasat, Mahidol University Bangkok; Kazuyasu Mori, Emory University; Francois Villinger, Emory University; Aftab A Ansari, Emory University
• Journal Title: Immunology
• Volume: Volume 124, Number 2
• Publisher: Blackwell Science Inc | 2008-06, Pages 277-293
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1111/j.1365-2567.2007.02766.x
• Subjects: Health Sciences, Immunology
• Keywords: immune response; PD-1; PD-L1; simian immunodeficiency virus; T cells

Abstract

Phenotypic and functional studies of the programmed death-1 (PD-1) molecule on CD4+ and CD8+ T cells were performed on peripheral blood mononuclear cells from uninfected and simian immunodeficiency virus (SIV)-infected rhesus macaques. These data demonstrated a rapid upregulation of PD-1 expression on tetramer-positive CD8+ T cells from MamuA.01+ SIV-infected macaques upon infection. Upregulation of PD-1 on total CD8+ T cells was not detectable. In contrast, CD4+ T-cell PD-1 expression was markedly higher in total CD4+ T cells during chronic, but not acute, infection and there was a correlation between the level of PD-1 expression on naive and central memory CD4+ T cells and the levels of viral loads. Such association was emphasized further by a marked decrease of PD-1 expression on tetramer-positive CD8 T cells as well as on CD4+ T cells on longitudinal samples collected before and after the initiation of antiretroviral therapy and downregulation of viral replication in vivo. Cloning of PD-1 and its two ligands from several non-human primate species demonstrated > 95% conservation for PD-1 and PD-L2 and only about 91% homology for PD-L1. Functional studies using soluble recombinant PD-1 protein or PD-1–immunoglobulin G fusion proteins induced marked increases in the SIV-specific proliferative responses of both CD4+ and CD8+ T cells from rhesus macaques. The results of these studies serve as a foundation for future in vivo trials of the use of rMamu-PD-1 to potentially enhance and/or restore antiviral immune responses in vivo.