Restored function of HBV-specific T cells after long-term effective therapy with nucleos(t)ide analogues.
OBJECTIVE
In patients with chronic hepatitis B virus (HBV) infection, persistent exposure to high concentrations of antigen can disrupt T-cell functions. It is not clear to what extent long-term suppression of HBV by nucleos(t)ide analogues can restore antiviral T-cell functions. We compared HBV-specific T-cell responses of patients treated with nucleos(t)ide analogues with those detected in other conditions of HBV control.


METHODS
We analyzed intracellular levels of interferon gamma, interleukin-2, and tumor necrosis factor α in HBV-specific T cells after 10 days of stimulation with peptides covering the overall HBV genotype D sequence and ex vivo with selected CD8 epitopes and the corresponding HLA-A2 dextramers. Findings from patients treated with nucleos(t)ide analogues who had complete (HBV DNA negative/antibody to hepatitis B surface antigen positive) or partial (HBV DNA negative/hepatitis B surface antigen positive) control of their infections were compared with those of patients with spontaneous or interferon alfa-induced resolution of acute or chronic infections, inactive HBV carriers, or untreated hepatitis B e antigen-negative patients with chronic infections.


RESULTS
Although HBV-specific T cells from nucleos(t)ide analogue-treated patients with complete control of infection were dysfunctional ex vivo, they had efficient responses after in vitro expansion. These responses were comparable to those of patients who spontaneously resolved acute HBV infection. Nucleos(t)ide analogue-treated patients who were HBV DNA negative but hepatitis B surface antigen positive had lower levels of T-cell responses but responses greater than those of untreated patients with chronic infection.


CONCLUSIONS
In vitro reactivity can be restored to T cells from patients with suppressed HBV infection following long-term treatment with nucleos(t)ide analogues, despite prolonged exposure to large loads of antigen. Immune therapies that increase the antiviral T-cell response might increase the likelihood of complete HBV control in patients undergoing long-term nucleos(t)ide analogue treatment.
Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy.
Carolina
C
Boni
Diletta
D
Laccabue
Pietro
P
Lampertico
Tiziana
T
Giuberti
Mauro
M
Viganò
Simona
S
Schivazappa
Arianna
A
Alfieri
Marco
M
Pesci
Giovanni B
GB
Gaeta
Giuseppina
G
Brancaccio
Massimo
M
Colombo
Gabriele
G
Missale
Carlo
C
Ferrari
D000225:Adenine / Q000031:analogs & derivatives / Q000627:therapeutic use; D000998:Antiviral Agents / Q000627:therapeutic use*; D002478:Cells, Cultured; D004279:DNA, Viral / Q000097:blood; D005838:Genotype; D006147:Guanine / Q000031:analogs & derivatives / Q000627:therapeutic use; D006514:Hepatitis B Surface Antigens / Q000097:blood; D006513:Hepatitis B e Antigens / Q000097:blood; D006515:Hepatitis B virus / Q000235:genetics / Q000276:immunology*; D019694:Hepatitis B, Chronic / Q000097:blood / Q000188:drug therapy*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D007375:Interleukin-1 / Q000378:metabolism; D019259:Lamivudine / Q000627:therapeutic use; D063065:Organophosphonates / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000378:metabolism*; D000068698:Tenofovir; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000998:Antiviral Agents; D004279:DNA, Viral; D006514:Hepatitis B Surface Antigens; D006513:Hepatitis B e Antigens; D007375:Interleukin-1; D063065:Organophosphonates; D014409:Tumor Necrosis Factor-alpha; D019259:Lamivudine; C413685:entecavir; D006147:Guanine; D007371:Interferon-gamma; D000068698:Tenofovir; D000225:Adenine; C106812:adefovir dipivoxil