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
Open Access
- 15 September 2011
- journal article
- Published by The American Association of Immunologists
- Vol. 187 (6), 2932-2943
- https://doi.org/10.4049/jimmunol.1100594
Abstract
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.Keywords
This publication has 51 references indexed in Scilit:
- IL-28B/IFN-λ3 Drives Granzyme B Loading and Significantly Increases CTL Killing Activity in MacaquesMolecular Therapy, 2010
- Ki‐67 staining for determination of rhesus macaque T cell proliferative responses ex vivoCytometry Part A, 2010
- siRNA Knockdown of PD-L1 and PD-L2 in Monocyte-Derived Dendritic Cells only Modestly Improves Proliferative Responses to Gag by CD8+ T Cells from HIV-1-Infected IndividualsJournal of Clinical Immunology, 2009
- Lytic Granule Loading of CD8+ T Cells Is Required for HIV-Infected Cell Elimination Associated with Immune ControlImmunity, 2008
- PDL-1 upregulation on monocytes and T cells by HIV via type I interferon: Restricted expression of type I interferon receptor by CCR5-expressing leukocytesClinical Immunology, 2008
- Immunogenicity of novel consensus-based DNA vaccines against Chikungunya virusVaccine, 2008
- Reinvigorating exhausted HIV-specific T cells via PD-1–PD-1 ligand blockadeThe Journal of Experimental Medicine, 2006
- PD-1 is a regulator of virus-specific CD8+ T cell survival in HIV infectionThe Journal of Experimental Medicine, 2006
- HIV/AIDS epidemiology, pathogenesis, prevention, and treatmentThe Lancet, 2006
- Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infectionNature, 1995