Temporal analysis of early immune responses in patients with acute hepatitis B virus infection.
OBJECTIVE
Hepatitis B virus (HBV) causes more than 1 million deaths annually from immune-mediated liver damage. The long incubation period has been difficult to study; by the time most patients present, massive viremia and the majority of viral clearance have already occurred. The aim of this study was to investigate the contribution of innate and adaptive immune mechanisms in early acute HBV through access to an unusual cohort of patients sampled in the preclinical phase and followed up to resolution of their infection.


METHODS
Twenty-one patients with acute HBV were studied, 8 of them from before the peak of viremia. Circulating innate cytokines were quantitated by enzyme-linked immunosorbent assay and natural killer (NK) and T-cell effector function by flow cytometry. Results were correlated with temporal changes in viral load, serology, and liver inflammation and compared with healthy controls.


RESULTS
Type I interferon (IFN) remained barely detectable throughout, with concentrations no higher than those found in healthy controls. Similarly, interleukin-15 and IFN-lambda1 were not induced during peak viremia. NK cell activation and capacity for IFN-gamma production were reduced at peak viremia. Early functional HBV-specific CD4 and CD8 T-cell responses were attenuated as viral load increased and recovered again as infection resolved. The transient inhibition of NK and T-cell responses coincided with a surge in the immunosuppressive cytokine interleukin-10 accompanying HBV viremia.


CONCLUSIONS
The early stages of acute HBV are characterized by induction of interleukin-10 rather than type I IFN, accompanied by a temporary attenuation of NK and T-cell responses.
Dunn
Claire
C
Division of Infection and Immunity, University College London, London, England.
Peppa
Dimitra
D
Khanna
Pooja
P
Nebbia
Gaia
G
Jones
Meleri
M
Brendish
Nathan
N
Lascar
R Monica
RM
Brown
David
D
Gilson
Richard J
RJ
Tedder
Richard J
RJ
Dusheiko
Geoffrey M
GM
Jacobs
Michael
M
Klenerman
Paul
P
Maini
Mala K
MK
D000208:Acute Disease; D000328:Adult; D000998:Antiviral Agents / Q000627:therapeutic use; D016207:Cytokines / Q000097:blood*; D005260:Female; D006509:Hepatitis B / Q000175:diagnosis / Q000188:drug therapy / Q000276:immunology*; D006515:Hepatitis B virus / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate; D007370:Interferon Type I / Q000097:blood; D007372:Interferons; D016753:Interleukin-10 / Q000097:blood; D019409:Interleukin-15 / Q000097:blood; D007378:Interleukins / Q000097:blood; D007694:Killer Cells, Natural / Q000276:immunology* / Q000821:virology; D008297:Male; D013601:T-Lymphocytes / Q000276:immunology* / Q000821:virology; D013997:Time Factors; D016896:Treatment Outcome; D019562:Viral Load; D014766:Viremia / Q000276:immunology; D000095022:Interferon Lambda
D000998:Antiviral Agents; D016207:Cytokines; D007370:Interferon Type I; D007372:Interferons; D016753:Interleukin-10; D019409:Interleukin-15; D007378:Interleukins; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C508609:IL10 protein, human