Decreased Survival of B Cells of HIV-viremic Patients Mediated by Altered Expression of Receptors of the TNF Superfamily

Abstract

Human immunodeficiency virus (HIV) infection leads to numerous perturbations of B cells through mechanisms that remain elusive. We performed DNA microarray, phenotypic, and functional analyses in an effort to elucidate mechanisms of B cell perturbation associated with ongoing HIV replication. 42 genes were up-regulated in B cells of HIV-viremic patients when compared with HIV-aviremic and HIV-negative patients, the majority of which were interferon (IFN)-stimulated or associated with terminal differentiation. Flow cytometry confirmed these increases and indicated that CD21low B cells, enhanced in HIV-viremic patients, were largely responsible for the changes. Increased expression of the tumor necrosis factor (TNF) superfamily (TNFSF) receptor CD95 correlated with increased susceptibility to CD95-mediated apoptosis of CD21low B cells, which, in turn, correlated with HIV plasma viremia. Increased expression of BCMA, a weak TNFSF receptor for B lymphocyte stimulator (BLyS), on CD21low B cells was associated with a concomitant reduction in the expression of the more potent BLyS receptor, BAFF-R, that resulted in reduced BLyS binding and BLyS-mediated survival. These findings demonstrate that altered expression of genes associated with IFN stimulation and terminal differentiation in B cells of HIV-viremic patients lead to an increased propensity to cell death, which may have substantial deleterious effects on B cell responsiveness to antigenic stimulation.

Two overrepresented B cell populations in HIV-infected individuals undergo apoptosis by different mechanisms

“…We described previously B cells from HIV-infected individuals that exhibited increased susceptibility to CD95L-mediated apoptosis; these cells reflected an overrepresented population of activated CD95 ϩ B cells expressing reduced levels of CD21 (8). More recently, we identified a second overrepresented population of CD10 ϩ B cells in HIV-infected individuals with advancing disease (11), a fraction of which also expressed reduced levels of CD21 (Fig.…”

“…We have demonstrated previously both in longitudinal and cross-sectional analyses that overrepresentation of a distinct B cell population, defined by reduced expression of CD21 and increased secretion of immunoglobulins (7), is likely to be responsible for several of the B cell defects that have been associated with ongoing HIV replication (8)(9)(10). Among the B cell alterations that correlate with HIV plasma viremia and decreased survival of B cells is an increased expression of CD95 accompanied by an increased susceptibility to CD95 ligand (CD95L)-mediated cell death (8).…”

“…The extrinsic pathway, initiated by the ligation of death receptors such as CD95 and other members of the TNF superfamily of receptors, is generally involved with removal of activated immune cells after they have performed their function or as a result of incomplete or inappropriate activation (19). In the setting of HIV disease and high plasma viremia, activated B cells also express high levels of CD95, leading to high susceptibility to CD95L-mediated apoptosis (8). The intrinsic or mitochondrial pathway of apoptosis, which is controlled by members of the Bcl-2 family, plays an important role in the ontogeny of B cells (20).…”

Loss of Discrete Memory B Cell Subsets Is Associated with Impaired Immunization Responses in HIV-1 Infection and May Be a Risk Factor for Invasive Pneumococcal Disease

“…The HIV-1 gp120 protein enhances BAFF production by macrophages (41) and increased serum BAFF levels are associated with progressive HIV-1 disease (42). Increased expression of B cell maturation Ag (one of the receptors for APRIL) and reduced levels of BAFF receptor have been linked to decreased survival of B cells in HIV-1 infection (31). It has been suggested that BAFF-induced polyclonal activation could lead to functional B cell exhaustion and impairment of humoral immune responses in HIV-1 infection (41).…”

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

“…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].…”