van Grevenynghe Julien, Procopio Francesco A, He Zhong, Chomont Nicolas, Riou Catherine, Zhang Yuwei, Gimmig Sylvain, Boucher Genevieve, Wilkinson Peter, Shi Yu, Yassine-Diab Bader, Said Elias A, Trautmann Lydie, El Far Mohamed, Balderas Robert S, Boulassel Mohamed-Rachid, Routy Jean-Pierre, Haddad Elias K, Sekaly Rafick-Pierre
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.
Nat Med. 2008 Mar;14(3):266-74. doi: 10.1038/nm1728. Epub 2008 Mar 2.
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.
中枢记忆CD4(+) T细胞（T(CM)细胞）的持续存在是HIV/AIDS免疫保护的主要相关因素，因为T(CM)细胞的下降速率可预测HIV疾病进展。在本研究中，我们发现，与来自病毒血症已成功治疗（ST）的受试者或HIV(-)供体的T(CM)和效应记忆CD4(+) T细胞（T(EM)细胞）相比，HIV(+)精英控制者（EC）受试者的T(CM)细胞和T(EM)细胞对Fas介导的凋亡更不易感，并且在多轮T细胞受体触发后持续时间更长。我们表明，EC受试者T(CM)细胞的持续存在是FOXO3a通路失活的直接结果。通过小干扰RNA或引入FOXO3a显性阴性形式（FOXO3a Nt）使转录活性形式的FOXO3a沉默，可将ST受试者T(CM)细胞的长期存活延长至与EC受试者T(CM)细胞相似的时长。FOXO3a在记忆细胞存活中的关键作用将有助于阐明控制EC受试者病毒复制的潜在免疫机制。
