This PPG will investigate the cellular, molecular and immunological properties of the cell surface inhibitory receptor programmed death-1 (PD-1) and how it functions during chronic viral infection. It is now well established that T cell dysfunction is a cardinal feature of many chronic viral infections and this is most strikingly seen during HIV infection. Recent studies have shown that the PD-1 inhibitory pathway plays a critical role in modulating this functional exhaustion of virus specific T cells. This has now been documented in several animal models such as murine LCMV infection and SIV infection of non-human primates and, more importantly, in humans during persistent infection with HIV, HBV and HCV. In addition to a role in regulating chronic viral infections, there is growing evidence that PD-1 plays an important role in tumors, autoimmunity and transplantation. However, despite PD-1's clear importance in maintenance of a healthy state little is known about PD-1 signaling and gene expression at the molecular level. With this in mind, the specific goals of this PPG are: 1) To elucidate the mechanisms of PD-1 function, signaling, and gene expression in healthy and HIV infected individuals and in model systems;and 2) To identify novel pathways, targets, and reagents that may be used to modify PD-1 expression and signaling in the treatment of immunological disease and viral infection. To achieve the above goals, we have assembled an outstanding team of investigators who will participate in the following four projects and three cores in this PPG: Project 1, PD-1 expression and HIV specific T cell dysfunction;Project 2, Regulation of PD-1 gene expression;Project 3, PD-1 signaling in T cells during chronic viral infection;Project 4, Targeting the PD-1 signaling pathway to rescue HIV T cell dysfunction. Taken together, these studies should provide insight into the mechanisms by which PD-1 regulates chronic viral infection and provide targets for therapeutic treatment of HIV infection. This molecular understanding of PD-1 function and regulation should also have implications for the treatment of tumors and autoimmunity, and for increasing the success of transplantation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI080192-05
Application #
8318860
Study Section
Special Emphasis Panel (ZAI1-PRJ-A (M1))
Program Officer
Embry, Alan C
Project Start
2008-09-22
Project End
2013-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
5
Fiscal Year
2012
Total Cost
$2,496,127
Indirect Cost
$330,245
Name
Emory University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Penaloza-MacMaster, Pablo; Kamphorst, Alice O; Wieland, Andreas et al. (2014) Interplay between regulatory T cells and PD-1 in modulating T cell exhaustion and viral control during chronic LCMV infection. J Exp Med 211:1905-18
Morou, Antigoni; Palmer, Brent E; Kaufmann, Daniel E (2014) Distinctive features of CD4+ T cell dysfunction in chronic viral infections. Curr Opin HIV AIDS 9:446-51
Xiao, Yanping; Yu, Sanhong; Zhu, Baogong et al. (2014) RGMb is a novel binding partner for PD-L2 and its engagement with PD-L2 promotes respiratory tolerance. J Exp Med 211:943-59
Lu, Peiyuan; Youngblood, Benjamin A; Austin, James W et al. (2014) Blimp-1 represses CD8 T cell expression of PD-1 using a feed-forward transcriptional circuit during acute viral infection. J Exp Med 211:515-27
Porichis, Filippos; Hart, Meghan G; Zupkosky, Jennifer et al. (2014) Differential impact of PD-1 and/or interleukin-10 blockade on HIV-1-specific CD4 T cell and antigen-presenting cell functions. J Virol 88:2508-18
Austin, James W; Lu, Peiyuan; Majumder, Parimal et al. (2014) STAT3, STAT4, NFATc1, and CTCF regulate PD-1 through multiple novel regulatory regions in murine T cells. J Immunol 192:4876-86
Céspedes, Pablo F; Bueno, Susan M; Ramírez, Bruno A et al. (2014) Surface expression of the hRSV nucleoprotein impairs immunological synapse formation with T cells. Proc Natl Acad Sci U S A 111:E3214-23
Porichis, Filippos; Hart, Meghan G; Zupkosky, Jennifer et al. (2013) In vitro assay to evaluate the impact of immunoregulatory pathways on HIV-specific CD4 T cell effector function. J Vis Exp :e50821
Youngblood, Ben; Noto, Alessandra; Porichis, Filippos et al. (2013) Cutting edge: Prolonged exposure to HIV reinforces a poised epigenetic program for PD-1 expression in virus-specific CD8 T cells. J Immunol 191:540-4
Scharer, Christopher D; Barwick, Benjamin G; Youngblood, Benjamin A et al. (2013) Global DNA methylation remodeling accompanies CD8 T cell effector function. J Immunol 191:3419-29

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