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

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 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.

Control of PD-L1 Expression by Oncogenic Activation of the AKT–mTOR Pathway in Non–Small Cell Lung Cancer

“…The dependence of PD-L1 translation on PI3K-AKT-mTOR activity is also observed during viral infections. In HIV-1-infected macrophages and dendritic cells, the viral protein Nef induces PD-L1 transcription by binding to the promoter but PD-L1 protein expression depends on active PI3K/AKT signaling (40). Our data indicate that multiple types of stimuli, including growth factors cytokines and oncogenes, converge at mTOR to increase PD-L1 expression.…”

Posttranscriptional Control of PD-L1 Expression by 17β-Estradiol via PI3K/Akt Signaling Pathway in ERα-Positive Cancer Cell Lines

“…One possible mechanism is that Akt inhibitor sensitizes the Akt plekstrin homology (PH) domain binding to phosphatidylinositol (3,4,5)-trisphosphate (PIP3), which facilitates membrane localization of Akt and induces conformational change of Akt, making it more susceptible to kinase phosphorylation or less susceptible to phosphatase dephosphorylation 44 . A previous study has shown that human immunodeficiency virus can activate PI3K/Akt to up-regulate PD-L1 expression 45 . Further, it has been shown that PI3K/Akt regulates PD-L1 expression at post-transcriptional levels 46 .…”

Co-Inhibitory Molecule Programmed Death-1 and Its Ligands: A New Alternative Therapy for Human Immunodeficiency Virus Infection?

“…PDL1 could be preferentially up-regulated in macrophages in an anti-inflammatory environment and PD-L2 might be predominantly up-regulated in a pro-inflammatory environment (Rodriguez-Garcia et al, 2011). HIV infection could also induce the expression of PD-L1 in DC (Muthumani et al, 2011). Additionally, PD-L1 overexpression has also been observed in T cell subsets of HIV infected individuals (Rosignoli et al, 2009), the mechanism by which this over-expression occurs remains poorly studied but, the over-expression of PD-1 ligands on T cells opens the possibility of a new T cell-T cell interaction that might be contributing to PD-1 upregulation.…”

“…The influence of the overexpression of these molecules on T cell functions has been clarified by using specific antibodies to block the interaction of PD-1 with its ligands (Finnefrock et al, 2009;Freeman et al, 2006). Blockade of the PD-1 pathway shows improvement in some T cell functions, enhances proliferation of HIV-specific CD4+ and CD8+ T cells and increases the secretion of some cytokines (Muthumani et al, 2011). Additionally, PD-1 expressed on monocytes might also be contributing to IL-10 production, which in turn favous T cell dysfunction (Said et al, 2010).…”

“…Accumulating evidence on the effect of PD-1 on T cells has increased the knowledge about the mechanisms of T cell exhaustion characteristic of chronic infections, placing PD-1 pathway as a novel strategy for HIV therapy (Porichis and Kaufmann, 2012). Several strategies are being developed for supporting the immune system not only in chronic viral infections but in other diseases affecting the immune system, some of them are: (1) blockade of PD-1/PD-L1 interaction with specific antibodies or trough other molecular approaches (Berger et al, 2008;Brahmer et al, 2010;Petrovas et al, 2006); (2) use of PD-1 blockade as an adjuvant in ART treatment or in vaccines trials (Finnefrock et al, 2009;Ha et al, 2008); (3) blockade of several inhibitory receptors expressed on T-specific exhausted cells Jin et al, 2010;Jones et al, 2008); and (4) use of iRNA for PD-L1 in APC (Muthumani et al, 2011).…”