Deleterious Effect of HIV-1 Plasma Viremia on B Cell Costimulatory Function

Abstract

HIV infection leads to numerous immunologic defects, including impaired B cell function. An effective humoral response requires bidirectional interactions between B cells and CD4+ T cells, critical of which are interactions between CD80/CD86 expressed on activated B cells and CD28 expressed on responder CD4+ T cells. In the present study, we examined the effect of active HIV replication on B cell costimulatory function. Induction of CD80/CD86 on B cells following B cell receptor and CD40 triggering and responsiveness of CD4+ T cells to activated B cells were investigated in a system where B cells of HIV-infected patients were compared concurrently to B cells of HIV-negative donors. In contrast to HIV-aviremic patients, B cells of HIV-viremic patients were ineffective at stimulating CD4+ T cells, as measured by the induction of activation markers and proliferation. The importance of interactions of CD80/CD86 and CD28 in activating CD4+ T cells was clear; the ablation of a normal response following the addition of neutralizing anti-CD86/CD80 Abs mirrored the response of CD4+ T cells to B cells of HIV-viremic patients, while the addition of exogenous CD28 ligands partially restored the poor CD4+ T cell response to the B cells of HIV-viremic patients. Ineffective B cell costimulatory function in HIV-viremic patients was associated with low induction of CD80/CD86 expression on B cells. Our findings further delineate the scope of defects associated with cognate B cell-CD4+ T cell interactions in HIV infection and suggest that therapeutic interventions designed to enhance CD28-dependent costimulatory pathways may help restore immune functions.

Mechanisms of hypergammaglobulinemia and impaired antigen-specific humoral immunity in HIV-1 infection

“…6,31 In the group of treatment-naive patients we observed that the percentage of circulating memory B lymphocytes is inversely correlated with HIV viremia, indicating that virus-induced immune activation may directly contribute to the loss of memory B cells and to B-cell dysfunctions, as recently suggested. 24 On the other hand and perhaps simultaneously, high antigenic pressure might be a bystander driving force to activate B cells to produce polyclonal Abs. 25 The B-cell hyperactivity found in our and previous studies can be considered as a paradox since a poor B-cell response occurs in patients after immunization.…”

“…17,22 In addition, HIV-1 itself may directly affect B-cell activation and dysfunction, inducing the appearance of a subset of CD21 Ϫ B cells which have been proposed to contribute to increased antibody production. 23,24 A recent work by Hunziker et al 25 has suggested that naive B cells represent an important source of hypergammaglobulinemia and autoantibody production in chronic viral infections.…”

“…17,22 In addition, HIV-1 itself may directly affect B-cell activation and dysfunction, inducing the appearance of a subset of CD21 Ϫ B cells which have been proposed to contribute to increased antibody production. 23,24 A recent work by Hunziker et al 25 has suggested that naive B cells represent an important source of hypergammaglobulinemia and autoantibody production in chronic viral infections.Because of the lack of protective humoral immunity, HIV-1-infected individuals receive vaccination against several pathogens. However, many studies have reported an impaired humoral immune response in most of the patients after vaccination.…”

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

“…Several studies have demonstrated that after reduction of HIV plasma viremia by antiretroviral therapy, B cell abnormalities subside, especially those thought to be directly or indirectly associated with virus-induced aberrant immune activation (4)(5)(6). 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).…”

Longitudinal analysis of B cell repertoire and antibody gene rearrangements during early HIV infection

“…A role for humoral immunity in this process is supported by the common development of hypergammaglobulinemia in chronically infected individuals, associated with B cell hyperactivation, clonal expansions and deletions, and deficient costimulatory function. [1][2][3][4][5][6] It is unclear, however, if these abnormalities are the result of viremia and a direct effect of virus on B lymphocytes or, alternatively, mediated by long-term infectioninduced changes in T-cell subsets and cytokine production. To assess the early effect of HIV infection on the integrity of the peripheral B cell repertoires, we analyzed the B cellreceptor diversity in a longitudinal cohort of 10 affected individuals who had been treated with HAART immediately after diagnosis and 10 infected individuals who chose not to be treated.…”