Transcription factor FOXO3a controls the persistence of memory CD4(+) T cells during HIV infection.
The persistence of central memory CD4(+) T cells (T(CM) cells) is a major correlate of immunological protection in HIV/AIDS, as the rate of T(CM) cell decline predicts HIV disease progression. In this study, we show that T(CM) cells and effector memory CD4(+) T cells (T(EM) cells) from HIV(+) elite controller (EC) subjects are less susceptible to Fas-mediated apoptosis and persist longer after multiple rounds of T cell receptor triggering when compared to T(CM) and T(EM) cells from aviremic successfully treated (ST) subjects or from HIV(-) donors. We show that persistence of T(CM) cells from EC subjects is a direct consequence of inactivation of the FOXO3a pathway. Silencing the transcriptionally active form of FOXO3a by small interfering RNA or by introducing a FOXO3a dominant-negative form (FOXO3a Nt) extended the long-term survival of T(CM) cells from ST subjects to a length of time similar to that of T(CM) cells from EC subjects. The crucial role of FOXO3a in the survival of memory cells will help shed light on the underlying immunological mechanisms that control viral replication in EC subjects.
van Grevenynghe
Julien
J
Laboratoire d'Immunologie, Centre de Recherche, Hôpital Saint-Luc, Centre Hospitalier de l'Université de Montréal, 264 Boulevard Rene-Levesque Est, Montréal, Québec H2X 1P1, Canada.
Procopio
Francesco A
FA
He
Zhong
Z
Chomont
Nicolas
N
Riou
Catherine
C
Zhang
Yuwei
Y
Gimmig
Sylvain
S
Boucher
Genevieve
G
Wilkinson
Peter
P
Shi
Yu
Y
Yassine-Diab
Bader
B
Said
Elias A
EA
Trautmann
Lydie
L
El Far
Mohamed
M
Balderas
Robert S
RS
Boulassel
Mohamed-Rachid
MR
Routy
Jean-Pierre
JP
Haddad
Elias K
EK
Sekaly
Rafick-Pierre
RP
D019380:Anti-HIV Agents / Q000627:therapeutic use; D023241:Antiretroviral Therapy, Highly Active; D017209:Apoptosis / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism*; D006801:Humans; D007156:Immunologic Memory; D019169:Jurkat Cells; D034741:RNA, Small Interfering; D014779:Virus Replication
D019380:Anti-HIV Agents; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D034741:RNA, Small Interfering