This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.This project seeks to evaluate the safety and therapeutic potential of in vivo blockade of interactions between the inhibitory receptor, PD-1 (Programmed death-1), and its ligands (PD-L1 and PD-L2) using a SIV/macaque model. Our hypothesis is that blockade of PD-1 interactions with its ligands can provide therapeutic benefit by eliciting cell-mediated immunity capable of providing better viral control than the functionally limited T cells characteristic of chronic SIV infections. Recent studies in mice persistently-infected with LCMV from Dr. Rafi Ahmed's laboratory (co-investigator of this proposal) have shown that the virus-specific CD8 and CD4 T cells upregulate expression of PD-1 following infection and that transient in vivo blockade of PD-1: PD-L1 interactions enhances the magnitude and functional quality of anti-viral T cells and improves viral control. Subsequent studies in HIV-infected people have documented that HIV-specific CD8 and CD4 T cells also upregulate expression of PD-1 and that in vitro blockade of PD-1 or PD-L1 enhances the proliferative capacity of these cells. Preliminary results from our laboratory demonstrate similar phenomena in SIV-infected macaques. Thus, in vivo blockade of PD-1: PD-1 ligand pathway may be able to enhance the control of immunodeficiency virus infections by increasing the magnitude and functional quality of virus-specific T cells, and might represent a new and powerful therapy for the control of HIV/AIDS. We will evaluate the safety and therapeutic potential of in vivo blockade of PD-1: PD-1 ligand pathway to control a chronic SIV251 infection in rhesus macaques. The mAb identified using in vitro blockade experiments will be used for in vivo blockade. We will also evaluate the therapeutic potential of in vivo blockade of PD-1: PD-1 ligand pathway in combination with anti-retroviral therapy (ART).
Showing the most recent 10 out of 912 publications
