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.
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Research Article AIDS/HIV

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

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Figure 4

Reduced IL-2 signaling resulted in premature memory B cell death in HIV+ subjects.

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Reduced IL-2 signaling resulted in premature memory B cell death in HIV+...
(A) IL-2 was measured in plasma samples from EC, ST, and HIV– subjects using ELISA (n ≥ 11 per group). (B) Correlation between the frequency of ex vivo memory B cell subsets within total B cells and plasma IL-2 levels in all subjects was also determined (n = 41; Spearman test). (C and D) Ex vivo PBMCs from ST, EC, and HIV– subjects were stained with 7AAD, anti-CD3–PB, anti-CD19–Alexa Fluor 700, anti-CD27–APC Cy7, and anti-CD25–PE (IL-2 receptor) to monitor their surface expression levels on gated viable memory B cells (n = 15). Results show (C) the frequencies of positive cells and (D) the expression levels of CD25 (MFI). (E) PBMCs from HIV+ and HIV– subjects were treated for 15 minutes with 10 ng/ml IL-2, then labeled with 7AAD, anti-CD3–PB, anti-CD19–Alexa Fluor 700, and anti-CD27–APC Cy7 Abs and then subjected to PhosFlow staining with anti-pSTAT5–PE Ab. Results show the levels of pSTAT5 within viable memory B cells (MFI; n = 15). Representative histograms for Figure 3, C and E, are also shown.