HIV mediated PI3K/Akt activation in antigen presenting cells leads to PD-1 ligand upregulation and suppression of HIV specific CD8 T-cells

• Published in: The Journal of immunology (1950) Vol. 187; no. 6; pp. 2932 - 2943
• Main Authors: Muthumani, Karuppiah, Shedlock, Devon J., Choo, Daniel K., Fagone, Paolo, Kawalekar, Omkar U., Goodman, Jonathan, Bian, Chaoran B., Ramanathan, Aarti A., Atman, Parikh, Tebas, Pablo, Chattergoon, Michael A., Choo, Andrew Y., Weiner, David B.
• Format: Journal Article
• Language: English
• Published: 19.08.2011
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1100594

Recent evidence demonstrates that HIV-1 infection leads to the attenuation of cellular immune responses, which has been correlated with the increased expression of programmed death 1 (PD-1) on virus-specific CD8 + T cells. PD-1 is induced upon T cell activation and its prolonged expression facilitates CD8 + T cell inhibitory signals when bound to its B7 family ligands, PD-L1/2, which are expressed on APCs. Importantly, early reports demonstrated that blockade of the PD-1/PD-L interaction by antibodies may help to counter the development of immune exhaustion driven by HIV viral persistence. To better understand the regulation of the PD-1 pathway during HIV infection, we examined the ability of the virus to induce PD-L expression on macrophages and dendritic cells. We found a direct relationship between the infection of APCs and the expression of PD-L1, in which virus-mediated upregulation induced a state of non-responsiveness in uninfected HIV-specific T cells. Furthermore, this exhaustion phenotype was revitalized by the blockade of PD-L1 after which T cells regained their capacity for proliferation and the secretion of proinflammatory cytokines IFN-γ, IL-2, and IL-12 upon restimulation. Additionally, we identify a critical role for the PI3K/Akt signaling pathway in PD-L1 upregulation of APC’s by HIV, as inhibition of these intracellular signal transducer enzymes significantly reduced PD-L1 induction by infection. These data identify a novel mechanism by which HIV exploits the immunosuppressive PD-1 pathway and suggest a new role for virus-infected cells in the local corruption of immune responses required for viral suppression.