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

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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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.

Original languageEnglish
Pages (from-to)3877-3888
Number of pages12
JournalJournal of Clinical Investigation
Volume121
Issue number10
DOIs
Publication statusPublished - Oct 3 2011

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ASJC Scopus subject areas

  • Medicine(all)

Cite this

Van Grevenynghe, J., Cubas, R. A., Noto, A., DaFonseca, S., He, Z., Peretz, Y., Filali-Mouhim, A., Dupuy, F. P., Procopio, F. A., Chomont, N., Balderas, R. S., Said, E. A., Boulassel, M. R., Tremblay, C. L., Routy, J. P., Sékaly, R. P., & Haddad, E. K. (2011). Loss of memory B cells during chronic HIV infection is driven by Foxo3a- and TRAIL-mediated apoptosis. Journal of Clinical Investigation, 121(10), 3877-3888. https://doi.org/10.1172/JCI59211