Differential Impact of PD-1 and/or Interleukin-10 Blockade on HIV-1-Specific CD4 T Cell and Antigen-Presenting Cell Functions

• Type of Material: Article
• Authors: Filppos Porichis, MIT and Harvard, Massachusetts General Hospital; Meghan G. Hart, MIT and Harvard, Massachusetts General Hospital; Jennifer Zupkosky, MIT and Harvard, Massachusetts General Hospital; Lucie Barblu, MIT and Harvard, Massachusetts General Hospital; Douglas S. Kwon, MIT and Harvard, Massachusetts General Hospital; Ashley McMullen, MIT and Harvard, Massachusetts General Hospital; Thomas Brennan, MIT and Harvard, Massachusetts General Hospital; Rafi Ahmed, Emory University; Gordon J. Freeman, Harvard University; David G. Kavanagh, MIT and Harvard, Massachusetts General Hospital; Daniel E. Kaufmann, MIT and Harvard, Massachusetts General Hospital
• Language: English
• Date: 2014-03-01
• Publisher: American Society for Microbiology
• Publication Version: Final Published Version
• Copyright Statement: © 2014, American Society for Microbiology.
• Final Published Version (URL): http://dx.doi.org/10.1128/JVI.02034-13
• Title of Journal or Parent Work: Journal of Virology
• ISSN: 0022-538X
• Volume: 88
• Issue: 5
• Start Page: 2508
• End Page: 2518
• Grant/Funding Information: The study was supported by the NIH (RO1 HL-092565; [D.E.K.]; P01 AI-080192 [R.A., D.E.K., D.G.K., and G.J.F.]; NIAID UM1AI100663; [CHAVI-ID] [D.E.K. and R.A.]; and P01 AI056299;, P01 AI078897;, and AI56299 [G.J.F.]).; D.E.K. is supported by a Career Award of the FRQS.; F.P. is supported by a fellowship grant of MGH and the Harvard Global Health Institute.
• Keywords: Life Sciences & Biomedicine; RECEPTOR; Science & Technology; EXHAUSTION; VIRAL-INFECTION; DISEASE PROGRESSION; HUMAN-IMMUNODEFICIENCY-VIRUS; DYSFUNCTION; HIV-INFECTION; VIROLOGY; CD154 EXPRESSION; Virology; IL-10; ACTIVATION
• Research Categories: Health Sciences, Immunology; Biology, Microbiology; Health Sciences, Oncology

Abstract

Antigen persistence in chronic infections and cancer upregulates inhibitory networks, such as the PD-1 and interleukin-10 (IL- 10) pathways, that impair immunity and lead to disease progression. These pathways are attractive targets for immunotherapy, as demonstrated by recent clinical trials of PD-1/PD-L1 blockade in cancer patients. However, in HIV-1 infection not all subjects respond to inhibition of either pathway and the mechanistic interactions between these two networks remain to be better defined. Here we demonstrate that in vitro blockade of PD-L1 and/or IL-10Rα results in markedly different profiles of HIV-1-specific CD4 T cell restoration. Whereas PD-L1 blockade leads to balanced increase in gamma interferon (IFN-γ), IL-2, and IL-13 secretion, IL-10Rα blockade preferentially restores IFN-γ production. In viremic subjects, combined PD-L1/IL-10Rα blockade results in a striking 10-fold increase in IFN-γ secretion by HIV-1-specific CD4 T cells that is not observed in subjects with spontaneous (elite controllers) or therapy-induced control of viral replication. In contrast to the dramatic increase in IFN-γ production, concurrent blockade has a marginal additive effect on IL-2 production, IL-13 secretion, and HIV-1-specific CD4 T cell proliferation. IFN-γ produced by T helper cells upregulates PD-L1, HLA I/II, and IL-12 expression by monocytes. The effect of combined blockade on IFN-γ was dependent on reciprocal reinforcement through IL-12. These studies provide crucial information on the different immunoregulatory qualities of PD-1 and IL-10 in progressive disease and link exhausted virus-specific CD4 T cells and monocytes in the regulation of IFN-γ and IL-12 secretion.