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

Abstract

The persistence of central memory CD4+ T cells (TCM cells) is a major correlate of immunological protection in HIV/AIDS, as the rate of TCM cell decline predicts HIV disease progression. In this study, we show that TCM cells and effector memory CD4+ T cells (TEM 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 TCM and TEM cells from aviremic successfully treated (ST) subjects or from HIV donors. We show that persistence of TCM 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 TCM cells from ST subjects to a length of time similar to that of TCM 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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Figure 1: Memory TCM and TEM cells from EC subjects are less sensitive to Fas-mediated apoptosis and show heightened in vitro persistence after multiple rounds of TCR stimulation compared to those from ST subjects or HIV donors.
Figure 2: mDCs from EC subjects, ST subjects and HIV subjects show similar phenotypic and functional patterns.
Figure 3: Ex vivo TCM and TEM cells from EC and ST subjects show similar profiles of activation and proliferation markers.
Figure 4: TCM and TEM from EC subjects display higher phospho-FOXO3a phenotypes than those from ST subjects and HIV subjects.
Figure 5: FOXO3a shutdown by siRNA rescues TCM and TEM cells from ST donors from Fas-mediated apoptosis.
Figure 6: FOXO3a Nt increases TCM cell persistence of ST subjects.

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Acknowledgements

We thank D. Trono (University of Geneva) for the lentiviral vector pWPI, packaging plasmid psPAX2 and envelope plasmid pMD2G. We thank M. Lainesse and Y. Chouikh for expert technical assistance. We thank L. Greller and R. Somogyi for statistical assistance. We also want to thank all study participants. J.v.G. is a recipient of the Fond de la Recherche Médicale fellowship, L.T. and E.A.S. are funded by the Canadian Institutes of Health Research and N.C. is supported by The American Foundation for AIDS Research (fellowship number 106634-38-RFRL). This study was supported by funds from the National Institutes of Health, the Canadian Institutes of Health Research, Genome Quebec, Genome Canada, Fonds de Recherche en Santé du Quebec and the Canadian Network for Vaccines and Immunotherapeutics. R.-P.S. is the Canada Research Chair in Human Immunology. J.-P.R., is a clinician-scientist supported by Fonds de Recherche en Santé du Quebec. We thank R. Seder, M. Lederman, Q. Eichbaum and P. Ancuta for critically reviewing the manuscript. We would also like to thank the members of the Cleveland Immunopathogenesis Consortium for helpful discussions.

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J.v.G. performed most of the experiments and wrote the article. R.-P.S. and E.K.H. generated the concept, supervised the experiments and wrote the article. F.A.P., Z.H., Y.Z. and Y.S. worked on the siRNA and lentiviral construct; N.C. did the p24 ELISA; B.Y.-D., E.A.S., L.T., M.E.F. and C.R. worked on the in vitro system; S.G. performed sorting; G.B. and P.W. worked on the statistics; and J.-P.R. and R.S.B. recruited subjects and helped with the discussion.

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Correspondence to Elias K Haddad or Rafick-Pierre Sekaly.

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van Grevenynghe, J., Procopio, F., He, Z. et al. Transcription factor FOXO3a controls the persistence of memory CD4+ T cells during HIV infection. Nat Med 14, 266–274 (2008). https://doi.org/10.1038/nm1728

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