Evidence for HIV-associated B cell exhaustion in a dysfunctional memory B cell compartment in HIV-infected viremic individuals

TLDR

HIV infection impairs B‑cell and antibody responses, and a distinct memory B‑cell subset (CD20^hi/CD27^lo/CD21^lo) expressing the inhibitory receptor FCRL4 has been identified in tonsillar tissue. This study characterizes a comparable FCRL4‑expressing B‑cell subset in the peripheral blood of viremic HIV‑positive individuals. In viremic patients, FCRL4 is up‑regulated on tissuelike memory B cells (CD20^hi/CD27^−/CD21^lo), which display exhausted phenotypes—poor proliferation, reduced immunoglobulin diversity, and expression of homing/inhibitory receptors—and are enriched for HIV‑specific responses, whereas classical memory B cells preferentially harbor influenza‑specific antibodies, indicating that premature B‑cell exhaustion may underlie suboptimal HIV antibody responses.

Abstract

Human immunodeficiency virus (HIV) disease leads to impaired B cell and antibody responses through mechanisms that remain poorly defined. A unique memory B cell subpopulation (CD20hi/CD27lo/CD21lo) in human tonsillar tissues was recently defined by the expression of the inhibitory receptor Fc-receptor-like-4 (FCRL4). In this study, we describe a similar B cell subpopulation in the blood of HIV-viremic individuals. FCRL4 expression was increased on B cells of HIV-viremic compared with HIV-aviremic and HIV-negative individuals. It was enriched on B cells with a tissuelike memory phenotype (CD20hi/CD27−/CD21lo) when compared with B cells with a classical memory (CD27+) or naive (CD27−/CD21hi) B cell phenotype. Tissuelike memory B cells expressed patterns of homing and inhibitory receptors similar to those described for antigen-specific T cell exhaustion. The tissuelike memory B cells proliferated poorly in response to B cell stimuli, which is consistent with high-level expression of multiple inhibitory receptors. Immunoglobulin diversities and replication histories were lower in tissuelike, compared with classical, memory B cells, which is consistent with premature exhaustion. Strikingly, HIV-specific responses were enriched in these exhausted tissuelike memory B cells, whereas total immunoglobulin and influenza-specific responses were enriched in classical memory B cells. These data suggest that HIV-associated premature exhaustion of B cells may contribute to poor antibody responses against HIV in infected individuals.