HIV causes global B cell dysregulation and restricts HBV-specific B cell development in an incident HBV cohort
Katherine E. Cascino, Thomas Liechti, Eric C. Seaberg, Kathleen Stevens, Steven M. Wolinsky, Mallory D. Witt, Robbie B. Mailliard, Mario Roederer, Justin R. Bailey, Chloe L. Thio, Andrea L. Cox
Katherine E. Cascino, Thomas Liechti, Eric C. Seaberg, Kathleen Stevens, Steven M. Wolinsky, Mallory D. Witt, Robbie B. Mailliard, Mario Roederer, Justin R. Bailey, Chloe L. Thio, Andrea L. Cox
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Clinical Research and Public Health Immunology Virology

HIV causes global B cell dysregulation and restricts HBV-specific B cell development in an incident HBV cohort

Abstract

BACKGROUND Functional B cell responses for both prevention and control of hepatitis B virus (HBV) infection remain poorly understood, including in the context of HBV/HIV coinfection.METHODS Here, we employed high-dimensional single-cell analysis to assess global and hepatitis B surface antigen–specific (HBsAg-specific) B cells in a longitudinal cohort of incident HBV from the Multicenter AIDS Cohort Study, with a subset of the cohort living with HIV-1.RESULTS We observed that prior HIV infection has negative consequences for B cell function in early post-acute HBV infection, including increased frequencies of atypical memory B cells and regulatory B cells, expression of the activation marker CD86 on multiple B cell subsets in chronic HBV (CHB), and restricted expansion of HBsAg-specific B cells. In contrast, in HBV monoinfection, we observed no changes in the global B cell population from prior to infection and robust expansion of HBsAg-specific B cells. These expanded antigen-specific B cells resembled class-switched intermediate and resting memory B cells, with activation phenotypes that may contribute to ongoing HBV control.CONCLUSION HIV infection has a significant impact on B cell responses to subsequent HBV infection that may promote development of CHB in HBV/HIV coinfection.FUNDING Vaccine Research Center, NIAID, Bill & Melinda Gates Foundation, and NIH.

Authors

Katherine E. Cascino, Thomas Liechti, Eric C. Seaberg, Kathleen Stevens, Steven M. Wolinsky, Mallory D. Witt, Robbie B. Mailliard, Mario Roederer, Justin R. Bailey, Chloe L. Thio, Andrea L. Cox

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Figure 1

Global B cell subsets are significantly altered in MWH.

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Global B cell subsets are significantly altered in MWH. (A) Schematic ov...
(A) Schematic overview of longitudinal HBV cohort. (B) Concatenated flow cytometry data depicted as UMAP of all B cells from preinfection samples and plotted for MWoH or MWH. Each dot represents a single B cell. All markers except the dump/viability and HBsAg probes were used to compute UMAP. Contour plots depict distribution of events on UMAP based on the equally sampled preinfection data. Yellow and purple arrows indicate areas of up- and downregulation in MWoH and MWH, respectively. (C) Frequencies of B cell subsets from MWoH (orange) and MWH (purple). (D) Representative MWoH participant (left plot) and MWH (right plot) from the preinfection time point were examined for expression of MBC subset markers CD27 and CD21. Frequencies of MBC subsets from all MWoH and MWH are shown below. (E) UMAP based on the composition of all B cells shown in C and D. Each dot represents 1 individual at preinfection time point. (F) Mean fluorescence intensity (MFI) of all phenotypic markers on MBC subsets based on CD21/CD27 expression profile from MWH pre-HBV infection. (G) Bubble plot highlights P values of all significant phenotypic marker expression (MFI) on MBCs between MWoH and MWH when compared using Wilcoxon’s signed-rank test. Dot size is based on –log10-transformed and unadjusted P values, and dot color is based on log2-transformed (upregulated in MWH, brown; MWoH, blue) fold-change. (B–F) Data from preinfection samples for MWoH (n = 32) and MWH (n = 44). (C and D) Data compared using Mann-Whitney U test and (F) Kruskal-Wallis test corrected for multiple comparisons, where each dot represents a single measurement from each individual assessed at the preinfection time point. Bars represent median values. *, P < 0.05; **, P < 0.01; ***, P < 0.001; ****, P < 0.0001.