Journal Article

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

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

2011

Overview

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.

• Publisher: American Society for Clinical Investigation
• Subject: Apoptosis / Apoptosis - immunology / B cells / B-Lymphocytes - immunology / B-Lymphocytes - metabolism / Biomedical research / Case-Control Studies / Cell Survival - immunology / Cells / Chronic Disease / Development and progression / Forkhead Box Protein O3 / Forkhead Transcription Factors - antagonists & inhibitors / Forkhead Transcription Factors - genetics / Forkhead Transcription Factors - metabolism / Health aspects / HIV / HIV infection / HIV Infections - immunology / HIV Infections - metabolism / HIV Infections - pathology / HIV Long-Term Survivors / HIV-1 / Homeostasis / Human immunodeficiency virus / Humans / Immunologic Memory / Infections / Interleukin-2 - blood / Interleukin-2 - pharmacology / Lymphocytes / Physiological aspects / RNA, Small Interfering - genetics / Signal Transduction / TNF-Related Apoptosis-Inducing Ligand - antagonists & inhibitors / TNF-Related Apoptosis-Inducing Ligand - metabolism