IMPAIRMENT OF B-LYMPHOCYTE DIFFERENTIATION-INDUCED BY DUAL TRIGGERINGOF THE B-CELL ANTIGEN RECEPTOR AND CD40 IN ADVANCED HIV-1-DISEASE

Objective: This study was performed to investigate the hyporeactivity of purified B lymphocytes from HIV-1-infected patients. Design: Given the importance of the B-cell Ag receptor (BCR) and CD40 in B-lymphocyt e activation, we assessed the capacity of purified peripheral blood B lymphocytes from HIV-1-infected patients to differentiate into Ig-secr eting cells in a T-cell- and accessory-cell-independent system of BCR and CD40 costimulation. Methods: B lymphocytes from 21 HIV-1-infected patients were purified by immunomagnetic cell separation and costimula ted with immobilized anti-CD40 monoclonal antibodies and Staphylococcu s aureus Cowan I particles in the presence of interleukin (IL)-2 and I L-10. Homotypic aggregate formation, apoptosis, cell cycle entrance, p roliferation and Ig secretion of B cells were analysed. Results: Costi mulation by the BCR and CD40 induced proliferation and differentiation of B lymphocytes into Ig-secreting cells in 13 patients (group I) but not in eight patients (group II). For three patients in group II, the dual triggering induced apoptosis of B cells. The unexpected inabilit y of these cells to differentiate was associated with a high CD38 expr ession and a weak spontaneous production of Ig or anti-HIV-1 antibodie s in patients with a high viral load and a low CD4+ lymphocyte count. Despite this anomaly, the B cells from group II were able to progress through the cell cycle after stimulation with a combination of phorbol ester and ionomycin in complete medium, suggesting an impairment in B CR and CD40 early signal transduction. Conclusion: Intrinsic in vitro hyporeactivity of B lymphocytes to dual triggering of BCR and CD40 was observed in advanced HIV-1 disease and appeared to be related to in v ivo hyperactivation of B cells. (C) 1998 Lippincott-Raven Publishers.