title: 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.affiliation: Vaccine and Gene Therapy Institute - Florida, Port St. Lucie, Florida, USA.
authors.forename: Julien
authors.initials: J
authors.lastname: van Grevenynghe
authors.forename: Rafael A
authors.initials: RA
authors.lastname: Cubas
authors.forename: Alessandra
authors.initials: A
authors.lastname: Noto
authors.forename: Sandrina
authors.initials: S
authors.lastname: DaFonseca
authors.forename: Zhong
authors.initials: Z
authors.lastname: He
authors.forename: Yoav
authors.initials: Y
authors.lastname: Peretz
authors.forename: Abdelali
authors.initials: A
authors.lastname: Filali-Mouhim
authors.forename: Franck P
authors.initials: FP
authors.lastname: Dupuy
authors.forename: Francesco A
authors.initials: FA
authors.lastname: Procopio
authors.forename: Nicolas
authors.initials: N
authors.lastname: Chomont
authors.forename: Robert S
authors.initials: RS
authors.lastname: Balderas
authors.forename: Elias A
authors.initials: EA
authors.lastname: Said
authors.forename: Mohamed-Rachid
authors.initials: MR
authors.lastname: Boulassel
authors.forename: Cecile L
authors.initials: CL
authors.lastname: Tremblay
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Routy
authors.forename: Rafick-Pierre
authors.initials: RP
authors.lastname: Sékaly
authors.forename: Elias K
authors.initials: EK
authors.lastname: Haddad
mesh_terms: D017209:Apoptosis / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D016022:Case-Control Studies; D002470:Cell Survival / Q000276:immunology; D002908:Chronic Disease; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015658:HIV Infections / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D020276:HIV Long-Term Survivors; D015497:HIV-1; D006801:Humans; D007156:Immunologic Memory; D007376:Interleukin-2 / Q000097:blood / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C508594:IL2 protein, human; D007376:Interleukin-2; D034741:RNA, Small Interfering; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human