Abstract
Background:Hepatitis B virus (HBV) affects up to 400 million people worldwide and accounts for approximately one million deaths per year from liver pathologies. Current treatment regimens are effective in suppressing viremia but usually have to be taken indefinitely, warranting research into new therapeutic approaches. Acute HBV infection in adults almost universally results in resolution of viremia, with the exception of immunocompromised persons, suggesting that the immune response can functionally cure or even eradicate HBV infection.Methods:Because immunophenotypic and functional studies have implicated a role for Natural Killer (NK) cells in HBV clearance during acute infection, we hypothesized that a distinct NK-cell profile exists in acute HBV infection that could provide information for the mechanism of HBV clearance. Using multivariate flow cytometry, we evaluated the expression of key activating and inhibitory receptors on NK cells, and their ability to respond to classic target cell lines.Results:Multivariate analysis revealed selective perturbation of the CD56,dim NK-cell subset during acute infection, displaying low levels of NKp46+, NKp30+, CD160+ and CD161+ cells. Intriguingly, the CD56,dim NK-cell profile predicted time to HBV surface antigen (HBsAg) clearance from the blood, and distinct NK-cell profiles predicted early (NKp30, CD94, CD161) and late clearance (KIR3DL1, CD158a, perforin, NKp46). Finally, functional analysis demonstrated that early and late clearance tracked with elevated degranulation (CD107a) or IFNγ production, respectively, in response to ADCC-mediated activation.Conclusion:The cytolytic CD56,dim NK-cell subset is selectively activated in acute HBV infection and displays distinct phenotypic and functional profiles associated with efficient and early control of HBV, implicating antibody-mediated cytolytic NK-cell responses in the early control and functional cure of HBV infection.
Highlights
Hepatitis B virus (HBV) affects up to 400 million people worldwide and accounts for approximately one million deaths per year from liver pathologies [1]
We demonstrate that acute HBV infection perturbs the more mature/cytolytic CD56dim but not the CD56bright Natural Killer (NK)-cell profile, and that early clearance of HBV surface antigen (HBsAg) can be predicted by a distinct CD56dim NK-cell phenotypic profile
Acute HBV infection elicits a distinct NK-cell profile in the CD56dim population NK-cell anti-viral responses are regulated by the interaction of multiple activating and inhibitory receptors with their ligands on virally infected cells
Summary
Hepatitis B virus (HBV) affects up to 400 million people worldwide and accounts for approximately one million deaths per year from liver pathologies [1]. Current treatment regimens are effective in suppressing viremia but rarely result in sustained control, after cessation of therapy, when the levels of HBV surface antigen (HBsAg) become undetectable and anti-HBsAg antibodies are developed [2]. The vast majority of adults who contract HBV elicit robust multi-cellular responses and control infection during the acute phase [4] and remain aviremic for life. This suggests that, HBV cccDNA might persist, a robust early immune response can provide long-term control, acting as a functional cure. Acute HBV infection in adults almost universally results in resolution of viremia, with the exception of immunocompromised persons, suggesting that the immune response can functionally cure or even eradicate HBV infection
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