TY - JOUR
T1 - Loss of memory B cells during chronic HIV infection is driven by Foxo3a- and TRAIL-mediated apoptosis
AU - Van Grevenynghe, Julien
AU - Cubas, Rafael A.
AU - Noto, Alessandra
AU - DaFonseca, Sandrina
AU - He, Zhong
AU - Peretz, Yoav
AU - Filali-Mouhim, Abdelali
AU - Dupuy, Franck P.
AU - Procopio, Francesco A.
AU - Chomont, Nicolas
AU - Balderas, Robert S.
AU - Said, Elias A.
AU - Boulassel, Mohamed Rachid
AU - Tremblay, Cecile L.
AU - Routy, Jean Pierre
AU - Sékaly, Rafick Pierre
AU - Haddad, Elias K.
PY - 2011/10/3
Y1 - 2011/10/3
N2 - 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.
AB - 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.
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U2 - 10.1172/JCI59211
DO - 10.1172/JCI59211
M3 - Article
C2 - 21926463
AN - SCOPUS:80053399756
SN - 0021-9738
VL - 121
SP - 3877
EP - 3888
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 10
ER -
