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HHV-6B infection, T-cell reconstitution, and graft-vs-host disease after hematopoietic stem cell transplantation

Abstract

Successful and sustained CD4+ T-cell reconstitution is associated with increased survival after hematopoietic cell transplantation (HCT), but opportunistic infections may adversely affect the time and extent of immune reconstitution. Human herpesvirus 6B (HHV-6B) efficiently infects CD4+ T cells and utilizes as a receptor CD134 (OX40), a member of the TNF superfamily that antagonizes regulatory T-cell (Treg) activity. Reactivation of HHV-6B has been associated with aberrant immune reconstitution and acute graft-versus-host disease (aGVHD) after HCT. Given that Treg counts are negatively correlated with aGVHD severity, we postulate that one mechanism for the poor CD4+ T-cell reconstitution observed shortly after transplant may be HHV-6B infection and depletion of peripheral (extra-thymic) CD4+ T cells, including a subpopulation of Treg cells. In turn, this may trigger a series of adverse events resulting in poor clinical outcomes such as severe aGVHD. In addition, recent evidence has linked HHV-6B reactivation with aberrant CD4+ T-cell reconstitution late after transplantation, which may be mediated by a different mechanism, possibly related to central (thymic) suppression of T-cell reconstitution. These observations suggest that aggressive management of HHV-6B reactivation in transplant patients may facilitate CD4+ T-cell reconstitution and improve the quality of life and survival of HCT patients.

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Acknowledgements

We are indebted with Kristin Loomis (HHV-6 Foundation) for facilitating the network among the authors of this study and for her continuous support of HHV-6 research. We would also like to acknowledge Hailey Allison for her assistance in the design of Fig. 1. This work was supported in part by the Intramural Program of the Division of Intramural Research, NIAID, NIH, by NIH grant 1R21AI111081-01A1 (to C.L.), and by a grant from the HHV-6 Foundation (to D.MK.).

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Phan, T.L., Pritchett, J.C., Leifer, C. et al. HHV-6B infection, T-cell reconstitution, and graft-vs-host disease after hematopoietic stem cell transplantation. Bone Marrow Transplant 53, 1508–1517 (2018). https://doi.org/10.1038/s41409-018-0225-2

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