TY - JOUR
T1 - HIV-mediated phosphatidylinositol 3-kinase/serine-threonine kinase activation in APCs leads to programmed death-1 ligand upregulation and suppression of HIV-specific CD8 T cells
AU - Muthumani, Karuppiah
AU - Shedlock, Devon J.
AU - Choo, Daniel K.
AU - Fagone, Paolo
AU - Kawalekar, Omkar U.
AU - Goodman, Jonathan
AU - Bian, Chaoran B.
AU - Ramanathan, Aarti A.
AU - Atman, Parikh
AU - Tebas, Pablo
AU - Chattergoon, Michael A.
AU - Choo, Andrew Y.
AU - Weiner, David B.
PY - 2011/9/15
Y1 - 2011/9/15
N2 - 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 (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-ligand (L)1/2, which are expressed on APCs. Importantly, early reports demonstrated that blockade of the PD-1/PD-L interaction by Abs 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 nonresponsiveness 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. In addition, we identify a critical role for the PI3K/serine-threonine kinase signaling pathway in PD-L1 upregulation of APCs by HIV, because 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.
AB - 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 (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-ligand (L)1/2, which are expressed on APCs. Importantly, early reports demonstrated that blockade of the PD-1/PD-L interaction by Abs 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 nonresponsiveness 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. In addition, we identify a critical role for the PI3K/serine-threonine kinase signaling pathway in PD-L1 upregulation of APCs by HIV, because 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.
UR - http://www.scopus.com/inward/record.url?scp=80053089977&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=80053089977&partnerID=8YFLogxK
U2 - 10.4049/jimmunol.1100594
DO - 10.4049/jimmunol.1100594
M3 - Article
C2 - 21856939
AN - SCOPUS:80053089977
SN - 0022-1767
VL - 187
SP - 2932
EP - 2943
JO - Journal of Immunology
JF - Journal of Immunology
IS - 6
ER -