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 2

Foxo3a regulated the premature death of memory B cells in ST subjects.

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Foxo3a regulated the premature death of memory B cells in ST subjects. P...
Purified memory B cells from ST subjects were either electroporated (electr.), or transfected with negative (neg.) siRNAs or with specific Foxo3a siRNAs, and then cocultured for 7 days with autologous CD19– PBMCs. (A) The efficacy of silencing Foxo3a using siRNAs was determined on purified memory B cells from ST subjects after 2 days of coculture using Western blot analysis. No changes were observed in the levels of total ERK expression, confirming the specificity of Foxo3a silencing. (B) Densitometric quantification of specific bands was performed using ImageQuant software (15, 17). The levels of expression of each protein were normalized to actin and were later expressed as the ratio of densitometric values of protein of interest divided by densitometric values of actin within the same blot. Results shown represent the mean relative expression ± SD of 5 independent experiments. (C) The levels of apoptosis in the presence or absence of Foxo3a were assessed on transfected memory B cells from ST subjects on day 7 by annexin V–APC staining (mean ± SD). The histograms shown are representative of raw data from 5 independent experiments.