PMID- 35716846
OWN - NLM
STAT- MEDLINE
DCOM- 20221019
LR  - 20221107
IS  - 1600-0641 (Electronic)
IS  - 0168-8278 (Linking)
VI  - 77
IP  - 5
DP  - 2022 Nov
TI  - Hepatitis B virus-specific CD4 T cell responses differentiate functional cure 
      from chronic surface antigen(+) infection.
PG  - 1276-1286
LID - S0168-8278(22)00366-X [pii]
LID - 10.1016/j.jhep.2022.05.041 [doi]
AB  - BACKGROUND & AIMS: With or without antiviral treatment, few individuals achieve 
      sustained functional cure of chronic hepatitis B virus (HBV) infection. A better 
      definition of what mediates functional cure is essential for improving 
      immunotherapeutic strategies. We aimed to compare HBV-specific T cell responses 
      in patients with different degrees of viral control. METHODS: We obtained blood 
      from 124 HBV-infected individuals, including those with acute self-limiting HBV 
      infection, chronic infection, and chronic infection with functional cure. We 
      screened for HBV-specific T cell specificities by ELISpot, assessed the function 
      of HBV-specific T cells using intracellular cytokine staining, and characterized 
      HBV-specific CD4 T cells using human leukocyte antigen (HLA) class II tetramer 
      staining, all directly ex vivo. RESULTS: ELISpot screening readily identified 
      HBV-specific CD4 and CD8 T cell responses in acute resolving infection compared 
      with more limited reactivity in chronic infection. Applying more sensitive assays 
      revealed higher frequencies of functional HBV-specific CD4 T cells, but not CD8 T 
      cells, in functional cure compared to chronic infection. Function independent 
      analysis using HLA multimers also identified more HBV-specific CD4 T cell 
      responses in functional cure compared to chronic infection, with the emergence of 
      CD4 T cell memory both after acute and chronic infection. CONCLUSIONS: Functional 
      cure is associated with higher frequencies of functional HBV-specific CD4 memory 
      T cell responses. Thus, immunotherapeutic approaches designed to induce HBV 
      functional cure should also aim to improve CD4 T cell responses. LAY SUMMARY: 
      Immunotherapy is a form of treatment that relies on harnessing the power of an 
      individual's immune system to target a specific disease or pathogen. Such 
      approaches are being developed for patients with chronic HBV infection, in an 
      attempt to mimic the immune response in patients who control HBV infection 
      spontaneously, achieving a so-called functional cure. However, what exactly 
      defines protective immune responses remains unclear. Herein, we show that 
      functional cure is associated with robust responses by HBV-specific CD4 T cells 
      (a type of immune cell).
CI  - Copyright (c) 2022 European Association for the Study of the Liver. Published by 
      Elsevier B.V. All rights reserved.
FAU - Hoogeveen, Ruben C
AU  - Hoogeveen RC
AD  - Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical 
      School, Boston, USA; Department of Gastroenterology and Hepatology, Erasmus MC, 
      University Medical Center, Rotterdam, the Netherlands.
FAU - Dijkstra, Suzan
AU  - Dijkstra S
AD  - Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical 
      School, Boston, USA.
FAU - Bartsch, Lea M
AU  - Bartsch LM
AD  - Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical 
      School, Boston, USA.
FAU - Drescher, Hannah K
AU  - Drescher HK
AD  - Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical 
      School, Boston, USA.
FAU - Aneja, Jasneet
AU  - Aneja J
AD  - Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical 
      School, Boston, USA; Division of Infectious Diseases, Massachusetts General 
      Hospital and Harvard Medical School, Boston, USA.
FAU - Robidoux, Maxwell P
AU  - Robidoux MP
AD  - Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical 
      School, Boston, USA.
FAU - Cheney, James A
AU  - Cheney JA
AD  - Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical 
      School, Boston, USA.
FAU - Timm, Joerg
AU  - Timm J
AD  - Institute of Virology, Heinrich Heine University, University Hospital, 
      Dusseldorf, Germany.
FAU - Gehring, Adam
AU  - Gehring A
AD  - Toronto Centre for Liver Disease, Toronto General Hospital Research Institute, 
      University Health Network, Toronto, Ontario, Canada; Department of Immunology, 
      University of Toronto, Toronto, Ontario, Canada.
FAU - de Sousa, Paulo Sergio Fonseca
AU  - de Sousa PSF
AD  - Instituto Oswaldo Cruz, Fundacao Oswaldo Cruz, Rio de Janeiro, Brazil.
FAU - Ximenez, Lya
AU  - Ximenez L
AD  - Instituto Oswaldo Cruz, Fundacao Oswaldo Cruz, Rio de Janeiro, Brazil.
FAU - Peliganga, Luis Baiao
AU  - Peliganga LB
AD  - Instituto Oswaldo Cruz, Fundacao Oswaldo Cruz, Rio de Janeiro, Brazil; Faculdade 
      de Medicina da Universidade Agostinho Neto, Luanda, Angola; Ministerio da Saude 
      de Angola, Luanda, Angola.
FAU - Pitts, Anita
AU  - Pitts A
AD  - Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical 
      School, Boston, USA.
FAU - Evans, Fiona B
AU  - Evans FB
AD  - Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical 
      School, Boston, USA.
FAU - Boonstra, Andre
AU  - Boonstra A
AD  - Department of Gastroenterology and Hepatology, Erasmus MC, University Medical 
      Center, Rotterdam, the Netherlands.
FAU - Kim, Arthur Y
AU  - Kim AY
AD  - Division of Infectious Diseases, Massachusetts General Hospital and Harvard 
      Medical School, Boston, USA.
FAU - Lewis-Ximenez, Lia L
AU  - Lewis-Ximenez LL
AD  - Instituto Oswaldo Cruz, Fundacao Oswaldo Cruz, Rio de Janeiro, Brazil.
FAU - Lauer, Georg M
AU  - Lauer GM
AD  - Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical 
      School, Boston, USA. Electronic address: glauer@mgh.harvard.edu.
LA  - eng
GR  - R01 AI148648/AI/NIAID NIH HHS/United States
GR  - U19 AI082630/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20220615
PL  - Netherlands
TA  - J Hepatol
JT  - Journal of hepatology
JID - 8503886
RN  - 0 (Antigens, Surface)
RN  - 0 (Antiviral Agents)
RN  - 0 (Cytokines)
SB  - IM
MH  - Antigens, Surface/therapeutic use
MH  - Antiviral Agents/therapeutic use
MH  - CD4-Positive T-Lymphocytes
MH  - CD8-Positive T-Lymphocytes
MH  - Cytokines
MH  - *Hepatitis B/drug therapy
MH  - Hepatitis B virus
MH  - *Hepatitis B, Chronic/drug therapy
MH  - Humans
OTO - NOTNLM
OT  - CD4 T cells
OT  - HLA multimer
OT  - Hepatitis B virus
OT  - T cell function
OT  - functional cure
COIS- Conflict of interest The authors declare no conflicts of interest that pertain to 
      this work. Please refer to the accompanying ICMJE disclosure forms for further 
      details.
EDAT- 2022/06/19 06:00
MHDA- 2022/10/20 06:00
CRDT- 2022/06/18 19:35
PHST- 2021/12/12 00:00 [received]
PHST- 2022/05/12 00:00 [revised]
PHST- 2022/05/25 00:00 [accepted]
PHST- 2022/06/19 06:00 [pubmed]
PHST- 2022/10/20 06:00 [medline]
PHST- 2022/06/18 19:35 [entrez]
AID - S0168-8278(22)00366-X [pii]
AID - 10.1016/j.jhep.2022.05.041 [doi]
PST - ppublish
SO  - J Hepatol. 2022 Nov;77(5):1276-1286. doi: 10.1016/j.jhep.2022.05.041. Epub 2022 
      Jun 15.