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

Abstract

The typical course of HIV infection for a majority of untreated individuals is persistent viral replication and a gradual loss of CD4 + T cells. One of the consequences of ongoing HIV replication is increased immune activation, aff ecting all major cell populations of the immune system ( 1 -3 ). Within the B cell population, HIV infection has been associated with numerous perturbations ( 4 ), many of which have been attributed to changes in the distribution of B cell subpopulations found in the peripheral blood. These changes include increased frequencies of activated and terminally diff erentiated B cells expressing low levels of CD21 that have been associated with ongoing viral replication ( 5, 6 ), a decreased frequency of memory B cells that is not reversed by antiretroviral therapy ( 7 ), and an increased frequency of immature/transitional B cells that has been associated with CD4 + T cell lymphopenia ( 8, 9 ).The eff ects of immune activation in persistent viral infections have recently been shown to include virus-specifi c T cell exhaustion. After the original description in chronic lymphocyte choriomeningitis virus (LCMV) infection in mice ( 10 ), observations of virus-specifi c CD4 + and CD8 + T cell exhaustion have recently been extended to 12 ). Although PD-1 was the fi rst inhibitory receptor associated with virus-specifi c T cell exhaustion, recent fi ndings suggest that exhaustion may result

Peripheral CD27−CD21− B-cells represent an exhausted lymphocyte population in hepatitis C cirrhosis

“…This B-cell subset has been found to exhibit lesser proliferation with BCR engagement plus CD40 ligation or BCR engagement plus TLR9 ligation, but the hypoproliferative "exhausted" phenotype could be partially overcome by combining all three stimuli [15,34]. We similarly found impaired proliferation in the CD27 − CD21 − B-cell subset with BCR stimulation alone and with CD40 stimulation, but partially recovered with combined BCR/CD40 stimulation.…”

“…An exhausted B-cell phenotype has been previously associated with a CD27 − CD21 lo "tissue-like memory" B-cell subset in HIV-infected subjects [15], a subset that has been variably associated with viral load and treatment status [32,33]. This B-cell subset has been found to exhibit lesser proliferation with BCR engagement plus CD40 ligation or BCR engagement plus TLR9 ligation, but the hypoproliferative "exhausted" phenotype could be partially overcome by combining all three stimuli [15,34].…”

“…Interestingly, FcRL4 was highly expressed on a small population of CD27 hi CD21 − that are likely plasmablasts [35], the significance of which needs further exploration. One possible mechanism of induction of an exhausted state could be chronic viral antigenic stimulation, as suggested in by the enrichment of HIVspecific B-cells in the CD27 − CD21 lo population in HIV-infected patients [15]. A second possible common mechanism between HIV infection and HCV infection and HCV-induced cirrhosis is chronic B-cell agonism by bacterial DNA or endotoxin associated with gut bacterial translocation [36,37].…”

“…A virus-specific anergic CD27 − CD21 − B-cell population has been described in HIV disease that may be identified by the expression of FcRL4 [14,15]. In common variable immunodeficiency, a tissue-homing peripheral CD21 lo B-cell population with impaired proliferation but exaggerated IgM secretory capacity with phenotypic similarities to the CD27 − CD21 lo B-cell population in HIV has also been described [16].…”

Immunologic characteristics of HIV‐infected individuals who make broadly neutralizing antibodies

“…It is possible that trafficking of the negative regulatory factor (Nef) protein from HIV‐1‐infected macrophages to B cells may alter class switching and germinal center (GC) responses,58 but dysfunction is also likely driven by the early cytokine storm59 and ongoing immune dysfunction caused by HIV‐1 infection of T cells. B‐cell dysregulation is evidenced by the delayed antibody response in acute HIV‐1 infection,41 an increase in the proportion of activated memory B cells and exhausted B cells, non‐specific plasmablast activation (leading to polyclonal immunoglobulin production), and a decline in the frequency of long‐lived plasma cells 42, 60, 61, 62, 63. In addition, Env‐specific B cells are found in the activated and exhausted B‐cell subsets in viremic individuals 64.…”