Considerations on human Herpesvirus 6 reactivation after cord blood transplantation
Authors: Tuan Phan, Danielle M. Zerr, Vicki Boussiotis, Paolo Lusso, Dario Di Luca
Journal: American Journal of Hematology (2018)

Recently, Rashidi et al. published an intriguing study highlighting an association between HHV-6 reactivation by day +28 post-cord blood transplantation (CBT) and an increase in disease relapse. They postulated that HHV-6 reactivation may have suppressed a possible graft-vs-tumor (GvT) effect by the allograft.1 This is arguably the largest and best-controlled study of HHV-6 reactivation and relapse reported to date, and we would like to share some of our observations and considerations for follow-up research. HHV-6 is the collective name for two viral species, HHV-6A and HHV-6B, which differ in several biological and pathogenic features. Rashidi et al. stated that the principal receptor for cell entry for HHV-6 is CD46, which indeed is the receptor used by HHV-6A to gain cellular entry. However, CD134 (OX40), an immunomodulatory molecule predominantly expressed on activated CD4+ cells, is the main receptor utilized for cell entry by HHV-6B, which is the most relevant HHV-6 species in the hematopoietic stem cell transplant (HCT) setting, particularly in cases involving acute GVHD (aGVHD).2 Thus, although the viral species responsible for the HHV-6 reactivation in the Rashidi study was not positively identified, HHV-6B was most likely involved in the majority of cases. In a study conducted at the same institution as that of Rashidi et al., CD4+ CD134+ T cells collected from CBT patients at day +28 post-CBT harbored significantly increased levels of HHV-6B DNA compared with T cells that had little or no expression of CD134.3 Furthermore, Nagamata et al. recently reported that CD134 expression was upregulated concurrently with the peak of HHV-6B DNA detection in alloHCT patients, and that the percentage of CD134+ cells decreased significantly when HHV-6B DNA was no longer detectable.4 It is highly likely that immunological processes involving HHV-6B correlate with the activity of CD134 as well. Rashidi et al. speculated that the HHV-6 reactivation may have suppressed a GvT effect, despite similar NK-cell and T-cell counts on day +28 in patients with and without HHV-6 reactivation. We have previously shown that herpesvirus infection does not alter NK-cell numbers, but rather it induces NK-cell anergy through expression of KIR2DL2.5 Thus, to effectively characterize NK-cell subsets, it would be critical to evaluate their activation status (CD69, CD107a) and KIR expression in addition to their frequency. Moreover, de Koning et al. recently reported that HHV-6 reactivation negatively affected late (thymus-dependent) CD4+ and CD8+ T-cell reconstitution (ie, after day +200) and not early (thymus-independent) T-cell reconstitution.6 CD4+ T-cell reconstitution was normal in patients who were given antivirals with efficacy against HHV-6. Consequently, the higher incidence of relapse in patients with HHV-6 reactivation reported by Rashidi et al. could be explained by diminished late, thymus-dependent T-cell reconstitution, possibly including Treg cells,7 which would not be detected by day +28. Providing an answer to these questions may offer important new insights into the pathogenesis of HCT failure and the role of HHV-6 in the setting of transplantation.