Transcription factor FOXO3a controls the persistence of memory CD4(+) T cells during HIV infection

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.
Nature medicine (Impact Factor: 28.05). 04/2008; 14(3):266-74. DOI: 10.1038/nm1728
Source: PubMed

ABSTRACT 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.

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Available from: Mohamed El-Far, Montreal, Oct 01, 2014
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    • "It has been known for some time that the quiescence state is actively maintained by factors such as LKLF, Tob, Foxo3a and Foxj1 (Coffer & Burgering, 2004; Tzachanis et al., 2004; Yusuf & Fruman, 2003). The role of these factors in HIV-latency has been explored by few laboratories so far (Haaland et al., 2005; van Grevenynghe et al., 2008) and further research may provide new insights into the mechanism of latency as well as potential therapeutic targets. "
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    • "Hence, this provides a molecular mechanism for how homeostatic signals regulate memory T cell persistence (Riou et al., 2007). Moreover, inhibition of Foxo3a expression has been shown to prolong human immunodeficiency virus-specific memory T cell survival, indicating that Foxo3a is a potential target for therapeutic intervention that could promote memory T cell establishment (Riou et al., 2007; van Grevenynghe et al., 2008). "
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