Immune trajectories of chronic and controlled Hepatitis B virus infection in HIV-uninfected and -infected individuals resolved by high-dimensional flow cytometry

Hepatitis B virus (HBV) infection causes chronic liver disease in ~5% of adults and is the major cause of hepatocellular carcinoma. Despite an effective vaccine, HBV remains a major health burden with 250 million cases globally. Co-infection with human immunodeficiency virus 1 (HIV-1) is common and accelerates disease progression. B cell responses are essential to control HBV infection, but the underlying immune mechanisms that determine disease outcome remain largely unknown.

We utilized 24-color flow cytometry to characterize longitudinal total and antigen-specific B cell signatures in blood associated with controlled versus chronic HBV infection, and to investigate the impact of HIV-1 co-infection on HBV-specific B cell responses. To this end, we analyzed HBV-only (N = 32) and HBV/HIV-1 (N = 44) co-infected individuals from the Multicenter AIDS Cohort Study before HBV infection, during acute infection and at early and late outcome timepoints. Patients were selected based on controlled versus chronic HBV infection. Data analysis included pre-processing using FlowAI and CytoNorm and manual gating and unsupervised data analysis to define B cell phenotypes.

HIV-1 co-infection led to increased B cell activation and regulatory B cell signatures in chronic HBV infection but not controllers. Thus, HIV-dependent B cell perturbations and elevated regulatory B cell activity may fuel immune activation during chronic HBV infection and explain the higher rate of chronic HBV infection in people with HIV-1. In contrast, robust elicitation of HBV-specific B cells only occured in HIV-negative HBV controllers. These cells displayed diverse phenotypes dominated by resting and activated memory B cells. Thus, we demonstrate that both HIV-1 co-infection and chronic HBV infection impair the development of effective B cell responses.

Overall, our study reveals divergent longitudinal global and HBV-specific B cell dynamics between chronic HBV infection and controllers and highlights how HIV-1 co-infection impacts B cell responses to HBV.

Thomas Liechti1*, Katherine Cascino2*, Eric C. Seaberg3, Kathleen Stevens2, Steven Wolinsky4, Mallory D. Witt5, Robbie B. Mailliard6, Mario Roederer1, Justin Bailey2, Chloe L Thio2¥, Andrea Cox2¥

1 ImmunoTechnology Section, Vaccine Research Center, NIAID, NIH, Bethesda, Maryland

2 Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland

3 Department of Epidemiology, Johns Hopkins University, Baltimore, Maryland

4 Division of Infectious Diseases, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois

5 Lundquist Research Institute at Harbor-UCLA Medical Center, Torrance, CA

6 Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania

¥*These authors contributed equally