Hepatitis B virus–specific T cells associate with viral control upon nucleos(t)ide-analogue therapy discontinuation
Laura Rivino, … , Patrick T.F. Kennedy, Antonio Bertoletti
Laura Rivino, … , Patrick T.F. Kennedy, Antonio Bertoletti
Published January 8, 2018
Citation Information: J Clin Invest. 2018;128(2):668-681. https://doi.org/10.1172/JCI92812.
View: Text | PDF
Clinical Research and Public Health Hepatology Immunology

Hepatitis B virus–specific T cells associate with viral control upon nucleos(t)ide-analogue therapy discontinuation

Abstract

BACKGROUND. The clinical management of chronic hepatitis B virus (HBV) patients is based exclusively on virological parameters that cannot independently determine in which patients nucleos(t)ide-analogue (NUC) therapy can be safely discontinued. NUCs efficiently suppress viral replication, but do not eliminate HBV. Thus, therapy discontinuation can be associated with virological and biochemical relapse and, consequently, therapy in the majority is life-long. METHODS. Since antiviral immunity is pivotal for HBV control, we investigated potential biomarkers for the safe discontinuation of NUCs within immune profiles of chronic HBV patients by utilizing traditional immunological assays (ELISPOT, flow cytometry) in conjunction with analyses of global non–antigen-specific immune populations (NanoString and CyTOF). Two distinct cohorts of 19 and 27 chronic HBV patients, respectively, were analyzed longitudinally prior to and after discontinuation of 2 different NUC therapy strategies. RESULTS. Absence of hepatic flares following discontinuation of NUC treatment correlated with the presence, during NUC viral suppression, of HBV core and polymerase-specific T cells that were contained within the ex vivo PD-1+ population. CONCLUSIONS. This study identifies the presence of functional HBV-specific T cells as a candidate immunological biomarker for safe therapy discontinuation in chronic HBV patients. Furthermore, the persistent and functional antiviral activity of PD-1+ HBV–specific T cells highlights the potential beneficial role of the expression of T cell exhaustion markers during human chronic viral infection. FUNDING. This work was funded by a Singapore Translational Research Investigator Award (NMRC/STaR/013/2012), the Eradication of HBV TCR Program (NMRC/TCR/014-NUHS/2015), the Singapore Immunology Network, the Wellcome Trust (107389/Z/15/Z), and a Barts and The London Charity (723/1795) grant.

Authors

Laura Rivino, Nina Le Bert, Upkar S. Gill, Kamini Kunasegaran, Yang Cheng, Damien Z.M. Tan, Etienne Becht, Navjyot K. Hansi, Graham R. Foster, Tung-Hung Su, Tai-Chung Tseng, Seng Gee Lim, Jia-Horng Kao, Evan W. Newell, Patrick T.F. Kennedy, Antonio Bertoletti

×

Figure 4

High-dimensional analyses by CyTOF of immune populations present in the peripheral blood of patients with and without evidence of flares upon therapy discontinuation.

Options: View larger image (or click on image) Download as PowerPoint
High-dimensional analyses by CyTOF of immune populations present in the ...
PBMCs from patients with and without flares upon therapy discontinuation were briefly stimulated with PMA/ionomycin, stained with a panel of 40 antibodies, and analyzed by CyTOF. (A) Live cells were concatenated after downsampling and analyzed in parallel by t-SNE (left panels). Manually gated lymphocyte populations were then overlaid onto the total t-SNE map (right panels). (B) Pie charts showing the average relative frequency of the different lymphocyte populations within the 2 groups of patients. (C) Heatmaps showing the average frequency of expression of each immunological marker within the indicated lymphocyte populations of patients that flared or did not flare upon therapy discontinuation. The percentages of positive expression are shown from low (black) to high (red). t-SNE plot shown in A shows 1 representative experiment. Data shown in B and C represent the average expression from 17 patients (n = 12 nonflare; n = 5 flare). All P values in C are greater than 0.05 as calculated by unpaired t test. See also Supplemental Figures 2 and 3.