Loss of memory B cells during chronic HIV infection is driven by Foxo3a- and TRAIL-mediated apoptosis
Julien van Grevenynghe, … , Rafick-Pierre Sékaly, Elias K. Haddad
Julien van Grevenynghe, … , Rafick-Pierre Sékaly, Elias K. Haddad
Published September 19, 2011
Citation Information: J Clin Invest. 2011;121(10):3877-3888. https://doi.org/10.1172/JCI59211.
View: Text | PDF | Corrigendum
Research Article AIDS/HIV Article has an altmetric score of 2

Loss of memory B cells during chronic HIV infection is driven by Foxo3a- and TRAIL-mediated apoptosis

Abstract

Loss of memory B cells occurs from the onset of HIV-1 infection and persists into the chronic stages of infection. Lack of survival of these cells, even in subjects being treated, could primarily be the consequence of an altered local microenvironment induced by HIV infection. In this study we showed that memory B cell survival was significantly decreased in aviremic successfully treated (ST) subjects compared with subjects who control viral load as a result of natural immunity (elite controller [EC]) or with uninfected control (HIV–) subjects. The lower survival levels observed in memory B cells from ST subjects were the result of disrupted IL-2 signaling that led to increased transcriptional activity of Foxo3a and increased expression of its proapoptotic target TRAIL. Notably, memory B cell survival in ST subjects was significantly enhanced by the addition of exogenous IL-2 in a Foxo3a-dependent manner. We further showed that Foxo3a silencing by siRNA resulted in decreased expression of TRAIL and apoptosis levels in memory B cells from ST subjects. Our results thus establish a direct role for Foxo3a/TRAIL signaling in the persistence of memory B cells and provide a mechanism for the reduced survival of memory B cells during HIV infection. This knowledge could be exploited for the development of therapeutic and preventative HIV vaccines.

Authors

Julien van Grevenynghe, Rafael A. Cubas, Alessandra Noto, Sandrina DaFonseca, Zhong He, Yoav Peretz, Abdelali Filali-Mouhim, Franck P. Dupuy, Francesco A. Procopio, Nicolas Chomont, Robert S. Balderas, Elias A. Said, Mohamed-Rachid Boulassel, Cecile L. Tremblay, Jean-Pierre Routy, Rafick-Pierre Sékaly, Elias K. Haddad

×

Figure 5

IL-2 treatment of memory B cells from ST subjects led to reduced levels of apoptosis by decreasing TRAIL expression.

Options: View larger image (or click on image) Download as PowerPoint
IL-2 treatment of memory B cells from ST subjects led to reduced levels ...
(A) Schematic showing the modulation of Foxo3a signaling pathway by IL-2 triggering. (B) Western blot analysis of memory B cells purified from ST subjects untreated or treated with 10 ng/ml of IL-2 for 15 minutes (pFoxo3a) or 24 hours (BimEL and TRAIL) (n = 5). The expression levels of actin were measured on the same blots to control for loading. (C) Densitometric quantification of specific bands was performed using ImageQuant software (mean ± SD). (D and E) Purified memory B cells from ST, EC, and HIV– subjects were cocultured for 7 days with autologous CD19– PBMCs in the presence or absence of 10 ng/ml IL-2 (n = 5). UNT, untreated. (D) Percentage of apoptosis ± SD on cocultured memory B cells (after 7 days) for all groups of subjects was determined by annexin V–APC. (E) Surface expression levels of TRAIL on memory B cells from ST subjects in the presence or absence of IL-2 at day 7 of coculture. Histograms shown are representative of 5 different ST subjects. (F) Correlation between surface expression of TRAIL and the percentage of apoptosis in memory B cells from ST subjects at day 7 of coculture in the presence or absence of IL-2 (n = 10; Spearman test).