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. Author manuscript; available in PMC: 2026 Mar 3.
Published in final edited form as: Bone Marrow Transplant. 2018 May 24;53(12):1508–1517. doi: 10.1038/s41409-018-0225-2

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

Tuan L Phan 1,2, Joshua C Pritchett 3, Cynthia Leifer 4, Danielle M Zerr 5,6, David M Koelle 7,8,9,10,11, Dario Di Luca 12, Paolo Lusso 13
PMCID: PMC12952197  NIHMSID: NIHMS2150555  PMID: 29795424

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.

Background

Allogeneic hematopoietic stem cell transplantation (alloHCT) is a critical therapeutic option for various hematologic malignancies and severe autoimmune disorders. Despite its efficacy, opportunistic infections remain the most common cause of morbidity and mortality in the haploidentical transplantation setting [1]. Human herpesvirus 6 (HHV-6) is a ubiquitous beta-herpesvirus that is often reactivated in immunosuppressed individuals, including alloHCT patients, and is the most common cause of post-transplant encephalitis after cord blood transplantation (CBT) [2]. HHV-6 was recently classified as two different viral species: HHV-6A and HHV-6B [3]. Both species have a tropism for CD4+ T cells and exert unique cytopathic effects on these cells [4–7]. While HHV-6A uses CD46, a ubiquitous complement-regulatory protein, as its receptor for cell entry [8], HHV-6B preferentially uses CD134 (also designated as OX40 or TNFRSF4), a receptor predominantly expressed on activated CD4+ T-lymphocytes [9, 10]. CD134 is an immunomodulatory molecule that blocks natural regulatory T-cell (Treg) activity and antagonizes the generation of inducible Treg cells [11]. CD134 has also been suggested to play a role in acute graft-versus-host disease (aGVHD) in transplant recipients [12–15].

The main functional and phenotypic T-cell subsets include CD4+ T cells (helper T cells), CD8+ T cells (cytotoxic T cells), and Treg cells. CD4+ T cells are typically “activated” when they are presented with peptide antigens by MHC class II molecules expressed on the surface of antigen-presenting cells (APCs; Fig. 1). Once activated, they proliferate rapidly and secrete cytokines that regulate or assist in the activation and maintenance of immune responses. CD8+ T cells usually recognize their targets by binding to antigens associated with MHC class I molecules and can directly destroy virus-infected cells by releasing the content of cytolytic granules (Fig. 1) or release antimicrobial factors such as antiviral cytokines [16]. Treg cells coexpress CD4, FOXP3, and CD25, and are typically derived from the same lineage as naive CD4+ T cells; their main function is to control or terminate cell-mediated immune responses and suppress autoreactive T cells. Through interleukin (IL)-10 and other immune mechanisms, Treg cells reduce the functional activity of autoreactive cells, including but not limited to CD8+ T cells (Fig. 1). As such, it is thought that Treg cells prevent the potential development of autoimmune diseases [17], including aGVHD [18].

Fig. 1.

Fig. 1

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Model of GVHD pathophysiology with or without HHV-6 reactivation. a Antigen-presenting cells (APCs) from the graft recipient or, in some cases, from the donor, activate donor CD4+ and CD8+ T cells, which proliferate and migrate to target organs, including the skin, GI tract, liver and hematopoietic system. Activated CD4+ T cells interact with APCs in the target organ tissue, causing tissue damage via release of inflammatory cytokines. Likewise, activated CD8+ T cells cause tissue damage by binding to APCs in target organs and releasing the content of cytotoxic granules. Regulatory T cells (Treg) can inhibit T-cell activation and proliferation via TGF-β and/or IL-10 release and other mechanisms, thereby mitigating the severity of aGVHD. b In cases where HHV-6B is reactivated after HSCT, we propose that the virus could deplete CD4+ T cells, including a subpopulation of Treg cells. As a result, HHV-6B reactivation would directly cause a reduction in CD4+ T cells and, indirectly, an increase in CD8+ T cells, which are not efficiently infected by HHV-6B, due to the lack of regulation by Treg cells. Ultimately, the imbalance in T-cell populations caused by HHV-6B reactivation would result in more severe aGVHD. This model may help to explain why de Pagter et al. [51] observed increased CD8+ T-cell proliferative responses without an associated CD4+ T-cell repsonse in patients with HHV-6 reactivation

Despite the lack of large clinical studies, several reports have associated HHV-6 reactivation with aGVHD after HCT [19–26], and a recent meta-analysis suggests that HHV-6 reactivation is predictive of subsequent grade 2–4 aGVHD [27]. However, the mechanism by which HHV-6 may contribute to aGVHD has not been ascertained. Furthermore, symptoms of severe HHV-6 reactivation [28] can be very similar to those of aGVHD [29], including fever, skin rash, and organ failure, which can result in misdiagnosis and unnecessary steroid or antiviral treatment. The purpose of this review is to assess published data on the relation among HHV-6B infection and T-cell depletion after HCT and evaluate them in light of recent findings to provide novel insights into the relationship between HHV-6B reactivation, CD4+ T-cell reconstitution, and development of clinical complications, such as aGVHD, in patients after transplant.

Biphasic T-cell reconstitution after allogeneic hematopoietic stem cell transplant

T-cell reconstitution after alloHCT is a lengthy process that proceeds simultaneously along two pathways with distinct kinetics [30]:

  1. In the first (thymus-independent) phase, which begins during the immediate post-transplant period, T-cell reconstitution takes place primarily in the periphery and is mediated by adoptively-transferred T cells or recipient T cells that have survived pre-transplant conditioning. These T-cell populations either undergo peripheral expansion in response to lymphopenia and high cytokine levels (primarily IL-7) or oligoclonal proliferation upon antigen interaction.

  2. The second (thymus-dependent) phase of T-cell reconstitution is a prolonged, multi-step process that can take up to 18 months after HSCT. In this phase, lymphomyeloid progenitor cells (LMPs) contained in the donor bone marrow (BM) or arising from successfully engrafted donor-derived HSCs migrate from the BM via circulation and repopulate the thymus with thymocyte precursors that can restart thymopoiesis. The thymus provides the essential microenvironment (stroma) for the newly arrived LMPs, which undergo continual proliferation, selection, and eventually differentiation into effective circulating T cells capable of broad antigenic specificity.

HHV-6 reactivation, which occurs commonly after HCT, could interfere with one or both of these pathways and jeopardize successful and sustained T-cell reconstitution, ultimately resulting in several potential downstream clinical complications.

In vitro and in vivo immunosuppressive effects of HHV-6 on CD4+ T cells

Both HHV-6A and HHV-6B have a direct tropism for immune cells and exert diverse immunomodulatory and immunosuppressive effects [31]. Both viruses productively infect CD4+ T cells and exert a strong cytopathic effect, including induction of apoptosis, both in vitro and in vivo [6, 32–34]. While HHV-6A can also efficiently infect cytotoxic effector cells like CD8+ T cells and NK cells, HHV-6B infects these cells very inefficiently, if at all [31]. These findings were corroborated by in vivo studies in patients with exanthema subitum [6], a disease primarily caused by HHV-6B [35]. Inoue et al. [33] demonstrated that HHV-6B indirectly induces apoptosis in CD4+ T lymphocytes in vitro, and Yasukawa et al. [32] subsequently supported this finding in vivo by observing apoptosis of peripheral blood lymphocytes isolated from infants with exanthema subitum and an adult patient with severe HHV-6 infection. Additionally, Ichimi et al. [36] reported the induction of apoptosis in HHV-6B-infected cord blood lymphocytes after stimulation with IL-2.

Another major immunomodulatory effect of HHV-6 occurs via modulation of cytokine production. Both HHV-6A and HHV-6B have been reported to reduce the synthesis of IL-2 [37, 38] and IL-12 [39], while enhancing the production of IL-1β, IL-10, interferon (IFN)-α, and tumor necrosis factor (TNF)-α [40–42]. Furthermore, both HHV-6 species were shown to exploit molecular mimicry to influence immune responses through the production of functional viral chemokines [43–45] and viral chemokine receptors [46].

Potential HHV-6B interactions in thymus-independent T-cell reconstitution during the early post-HCT period

It has been hypothesized that the delay or absence of immune reconstitution, especially of CD4+ T cells, creates an opportunity for endogenous reactivation of latent HHV-6B harbored in natural cellular reservoirs [47–49], leading to inflammation that could contribute to further dysfunctional engraftment and other clinical effects such as aGVHD [50]. However, this interpretation does not account for the fact that HHV-6B suppress CD4+ T-cell responses [42] and directly infects and depletes CD4+ T cells [6, 32–34]. Thus, direct infection of peripheral T cells by HHV-6B during the early post-HCT stage could be a cause, as well as a consequence, of the selective CD4+ lymphocytopenia during the early post-HCT period.

Using an assay that measures the proliferative capacity of HHV-6-specific CD8+and CD4+ T cells, de Pagter et al. [51] analyzed the quantitative and qualitative aspects of HHV-6-specific T-cell immunity after HCT. HHV-6-specific responses of CD8+T cells, but not of CD4+ T cells, were significantly increased in patients with HHV-6 reactivation compared to patients without HHV-6 reactivation. Although these authors focused on the CD8+ T-cell proliferative responses in their discussion, they did not consider the possibility that Treg cells could have been directly depleted by HHV-6 in their study, which, if true, would result in reduced suppression of alloreactive CD8+ T-cell responses (Fig. 1). Nonetheless, the authors concluded that prevention of HHV-6 reactivation may inhibit dysregulation of early immune reconstitution and potentially aGVHD.

Several case reports [52–54] and cohort studies [48, 55, 56] indicate that HHV-6 has the ability to deplete and reduce proliferation of CD4+ T cells in the clinical setting. In all cases where HHV-6 was genotyped, the prevalent species was HHV-6B or, in one report [54], a mixed infection. Michalek et al. [48] investigated the presence of HHV-6 DNA in 66 children with cancer and found that lymphopenia was associated with significant increases of HHV-6 DNA positivity (64.7% vs. 32.6%, p < 0.05). Sultanova et al. [55] studied 65 patients with gastrointestinal cancer before surgery and chemotherapy. They divided the cohort into two groups based on their lymphocyte count: group I (lymphocytes >1400 × 106/L, n = 35) and group II (lymphocytes <1400 × 106/L; n = 30) and observed that HHV-6B reactivation was more frequent in group II compared to group I (p < 0.05). Although the number of leukocytes was higher in patients with active HHV-6/−7 infection (p = 0.01), the number of CD4+ T lymphocytes in patients with active HHV-6/−7 infection was lower (p = 0.0002). It has been suggested that slow lymphocyte reconstitution might lead to profound lymphopenia after several chemotherapy cycles and, therefore, greater susceptibility to opportunistic infections and reactivation of latent viral reservoirs [48, 57]. However, given the ability of HHV-6 to infect CD4+ T cells, an alternative interpretation is that HHV-6 reactivation itself may contribute to lymphopenia, promoting a vicious cycle in which viral reactivation is exacerbated due to reduced T-cell immune surveillance [58].

Using a lymphocyte proliferation method that mainly detects activation of CD4+ T lymphocytes, Wang et al. detected HHV-6B-specific proliferative responses more often in patients without persistent HHV-6B infection than in those with persistent HHV-6B infection (defined as detection of HHV-6B in three consecutive PBL samples) after alloSCT (p < 0.001) [56]. Patients with persistent HHV-6 (not genotyped) viremia also had lower lymphocyte counts on the 8th week after transplantation than those without (p = 0.03). No HHV-6-specific proliferation responses were detected in the three patients who developed HHV-6 disease.

Taken together, the above studies highlight a number of potential interactions between HHV-6 and immune cell reconstitution during the early post-HCT period, which could ultimately lead to downstream clinical complications including aGVHD.

Potential HHV-6B interactions in thymus-dependent T-cell reconstitution during the late post-HCT period

While most authors have considered the potential effects of HHV-6 reactivation on T-cell reconstitution during the early post-HCT phase, a recent retrospective study by Admiraal et al. [19] reported an important effect of HHV-6 reactivation on long-term CD4+ T-cell recovery after HCT, which was not observable until approximately 200 days post-HCT. They observed that delayed CD4+ T-cell reconstitution was associated with viral reactivations, including adenovirus, Epstein-Barr virus (EBV), and HHV-6, with HHV-6 reactivation being the most frequent (27%; HHV-6 was not genotyped) [19]. In a follow-up paper [59], these same group reported that HHV-6-infected patients receiving antiviral drugs with anti-HHV-6 activity (i.e., foscarnet, ganciclovir, and cidofovir) experienced better late CD4+ T-cell reconstitution compared to patients who were not treated with anti-HHV-6 antivirals. These data strongly suggest an additional effect of HHV-6 during the thymus-dependent late phase after HCT. The temporal dissociation between HHV-6 reactivation, which tends to occur early, and the deficit in circulating CD4+ T cells detected at later time points after transplantation remains unexplained.

While the mechanism has not yet been fully characterized, further consideration of several known characteristics of HHV-6 immunobiology highlight a number of mechanisms whereby HHV-6 could directly disrupt central (intrathymic) T-cell reconstitution. In a humanized mouse model of HHV-6 infection, Gobbi et al. [60] demonstrated that both viruses efficiently infect human thymic tissue implanted in SCID-hu Thy/Liv mice, leading to the destruction of the graft. HHV-6A replication was associated with severe and progressive thymocyte depletion involving CD4+/CD8+, CD4+/CD8−, and CD4−/CD8+ subsets. Intrathymic T progenitor cells (ITTPs) appeared to be more severely depleted than the other subpopulations and a preferred tropism of HHV-6A for ITTPs was demonstrated by quantitative PCR on purified thymocyte subsets. In contrast to HHV-6A, a primary isolate of HHV-6B selectively depleted CD4+/CD8+ and CD4+/CD8− thymocytes, but did not affect the survival of CD4−/CD8+ cells [60], as expected, considering HHV-6B does not productively infect CD8+T cells [61]. Gobbi et al. [60] suggested that thymocyte depletion by HHV-6 may be due to infection and destruction of these immature T-cell precursors, while Takahashi et al. [6] suggested that HHV-6B predominantly infects T cells with a mature phenotype in cord blood mononuclear cells.

Additionally, previous studies in both mice [62] and humans [63] have identified expression of CD134 in thymocyte subpopulations, which could render these cells susceptible to infection by HHV-6B following virus reactivation after transplantation [9]. Once thymic cells become infected by HHV-6B (possibly including thymic epithelial/stromal cells), it is reasonable to hypothesize that post-HCT thymopoiesis—a complex process dependent upon interactions within the microenvironment of thymic stroma to properly select and propagate engrafted LMPs as outlined above—could be significantly hindered, resulting in poor long-term T-cell reconstitution as was reported by Admiraal et al. [19].

Finally, Patel et al. [64] recently identified a novel murine herpesvirus that is closely related to HHV-6. This virus, named murine roseolovirus due to the strong genomic resemblance to that of the human roseoloviruses (HHV-6/7), causes severe thymic necrosis in neonatal mice, characterized by significant subsequent loss of CD4+ T cells. If HHV-6B reactivation leads to similar effects in humans after HCT, the damage to thymic tissue could have devastating implications for subsequent thymus-dependent T-cell reconstitution.

Clinical consequences of dysfunctional T-cell reconstitution associated with HHV-6B reactivation

The main complications of acute GVHD after HCT include skin and GI dysfunction, delayed immune reconstitution, and issues typically associated with systemic steroid administration to treat GVHD, including viral and fungal infections. Of note, these infectious complications could also be related to the inflammatory milieu of GVHD itself, which is downstream of altered immune reconstitution [65]. In contrast, successful early CD4+ T-cell reconstitution is associated with increased survival after HCT [47, 66–70] and several studies have reported a significant correlation between CD4+ T-cell reconstitution and lower transplant-related mortality in alloHCT recipients [19, 66, 67, 69, 70]. Of note, Fedele et al. [69] reported that patients with early CD4+ T-cell reconstitution (CD4+counts >115/μL in blood samples collected at a median time of 20 days after transplant) had significantly lower rates of transplant-related mortality (14.5 ± 5% versus 39.4 ± 8%, p = 0.0027) and disease-related mortality (9.9 ± 4% vs. 38.7 ± 9%, p = 0.0029) after 2-year follow-up. Overall, survival was significantly affected by both aGVHD (hazard ratio (HR) 0.303, 95% confidence interval (CI) 0.107–0.860, p = 0.025) and having a circulating CD4+count >115/μL (HR 2.686 (95% CI 1.241–5.813, p = 0.012)). Given that HHV-6B reactivation is associated with aGVHD and delayed CD4+reconstitution, monitoring CD4+ T-cell recovery and HHV-6B reactivation after transplantation could identify patients at risk for development of aGVHD and allow for more targeted antiviral therapy [19, 71]. This strategy has proven to be effective for the prevention of human cytomegalovirus (CMV) reactivation [72, 73], as patients with adequate and functional CD4+ T-cell reconstitution are at lower risk for complications of viral reactivation and require less antiviral therapy.

In the retrospective study by Admiraal et al. [19], HHV-6 reactivation was a predictor of grade 2–4 aGVHD (HR 3.47, 95% CI 2.11–5.70, p < 0.0001). Furthermore, CD4+ T-cell reconstitution was associated with a protective effect from HHV-6-associated grade 2–4 GVHD; the frequency of GVHD in patients with HHV-6 reactivation and delayed immune reconstitution was 43% ± 9, while it was 31% ± 8 in patients with HHV-6 reactivation but without delayed immune reconstitution and 20% ± 3 in patients without HHV-6 reactivation (p = 0.0074). The authors’ initial assumption was that poor CD4+immune reconstitution was the cause of the increased HHV-6 reactivation and ensuing aGVHD. Subsequently, however, they considered the possibility that it was HHV-6 reactivation to determine a poor CD4+ T-cell immune reconstitution. They reported that HHV-6 reactivation significantly affects long-term CD4+ T-cell recovery, while short-term CD4+immune reconstitution was not affected [59, 74]. Moreover, HHV-6+ patients treated with ganciclovir, foscarnet, or cidofovir had normal long-term CD4+ T-cell recovery, whereas untreated HHV-6 + patients had significantly diminished long-term CD4+ T-cell recovery (p < 0.001) [59, 74]. Likewise, Quintela et al. [49] reported that HHV-6 infection was associated with significantly lower CD4+count 3 months after HCT (p = 0.023); however, no difference was observed at 6 or 12 months after HCT. It should be noted that 61.3% of their cohort received drugs with anti-HHV-6 activity (ganciclovir, foscarnet, or cidofovir), some of which are myelosuppressive (ganciclovir), complicating assessment of the possible causal relationship between HHV-6 reactivation and poor CD4+ T-cell reconstitution [49].

HHV-6B infection, Treg Cells, CD134, and graft-versus-host disease in alloHCT

The CD134 receptor has been implicated in GVHD pathophysiology [75]. Ge et al. [13] claimed that use of CD134-allodepleted grafts may improve alloHCT by reducing GVHD without loss of pathogen-specific and leukemia-specific immunity. Tsukada et al. [12] reported that the administration of an anti-CD134L monoclonal antibody significantly reduced the lethality of induced aGVHD in mice. Another study used methoxypolyethylene glycol-succinimidyl-propionic acid ester, a chemical modifier that binds to protein antigens on the surface of lymphocytes, and an anti-CD134L (OX40L) monoclonal antibody to relieve aGVHD in mice that underwent allo-BMT [14]. Both therapies ameliorated the symptoms of aGVHD and increased the survival rates in the experimental mice compared to controls. Furthermore, studies have reported that costimulatory signals from CD134 are antagonistic to FOXP3 induction in antigen-responding naive CD4+ T cells and suppress the development of CD25+FOXP3+-inducible Treg cells [11, 76, 77]. The CD134 ligand was shown to completely inhibit the generation of IL-10-producing type 1 Treg cells from naive and memory CD4+ T cells, despite treatment with immunosuppressants and stimulation with an inducible costimulatory ligand and immature dendritic cells [78]. Additionally, the CD134 ligand has been shown to strongly inhibit IL-10 production and the suppressive function of differentiated IL-10-producing type 1 Treg cells [78]. In vivo experiments using a mouse model of inflammatory bowel disease [79] and models of rejection of allogenic BM [80] and skin transplantation [76] have demonstrated that ligation of CD134 antagonizes the suppressive functions of Treg cells [17, 18]. The selective use of CD134 as a receptor for cell entry by HHV-6B may help to explain the special relationship between HHV-6B and the development of aGVHD [9]. CD4+ T cells expressing CD134 were reported to harbor significantly increased levels of HHV-6B DNA following CBT [81], and a recently published study of 23 alloHCT patients showed that CD134 expression correlated with HHV-6B reactivation [82]. Further research is required to determine the permissiveness of cells with a more completely defined Treg phenotype (e.g., CD4+CD25+CD39+CD127−) for HHV-6B infection in a variety of contexts, including primary and chronic infection in the immune competent, as in the case of drug-induced hypersensitivity [83], as well as during immune reconstitution.

Numerous studies have found HHV-6B to be the only virus consistently associated with aGVHD following HCT [20–22, 24, 25, 71]. A recent meta-analysis quantified the risk of aGVHD to be more than two times higher in patients with HHV-6B reactivation than without (HR 2.65, p < 0.001) [27]. When coupled with previous reports on the role of CD134 in GVHD pathophysiology, these data provide evidence in support of a causal pathway for HHV-6B in aGVHD.

Steroid treatment for GVHD can exacerbate HHV-6 reactivation after alloHCT

The administration of steroids to treat aGVHD could potentially amplify HHV-6 reactivation, which would result in a “snowball” effect of persistently increasing the severity of HHV-6-associated aGVHD (Fig. 2). The association between steroid administration and HHV-6 reactivation has been documented in alloHCT [24, 26, 84, 85] as well as in solid organ transplantation [86, 87]. Appleton et al. [88] reported that detection of HHV-6 DNA in GVHD-positive skin biopsies (obtained prior to or concomitantly with the onset of GVHD) was significantly associated with the development of severe GVHD; moreover, all four patients with steroid-refractory aGVHD were positive for HHV-6 DNA in skin biopsies. Pichereau et al. [23] analyzed a group of 19 patients grade 0–1 aGVHD but subsequently developed grade 2–4 aGVHD. They found that HHV-6 reactivation occurred simultaneously with or before the onset of aGVHD in the majority of cases and that GVHD was resistant to steroids in 11 of these 19 cases. HHV-6 reactivation may be a cause for steroid-refractory aGVHD and the “snowball” effect (Fig. 2) caused by steroid treatment could potentially explain the high mortality rate in steroid-refractory aGVHD [89]. Further studies specifically designed to address whether HHV-6 plays a role specifically in steroid-refractory aGVHD and whether antiviral treatment can disrupt the aforementioned “snowball” effect are needed.

Fig. 2.

Fig. 2

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“Snowball” effect due to GVHD treatment with steroids. Proposed model of the vicious cycle established by the combined effect of HHV-6B reactivation and steroid use in patients with aGVHD

Concluding remarks

Currently, the prevailing assumption is that the loss of CD4+ T cells in HCT patients underlies HHV-6B reactivation. As highlighted by the studies reviewed herein, an intriguing alternative interpretation is that immunosuppression from HCT leads to HHV-6B reactivation, which is then responsible for the depletion of CD4+ T cells, including a subpopulation of regulatory T cells, causing poor or unbalanced CD4+ T-cell reconstitution. This in turn would trigger a series of adverse events, including more severe inflammatory responses and viral reactivations, resulting in poor outcomes such as severe aGVHD (Fig. 1). This model supports a fundamental shift in the management of aGVHD, since early antiviral treatment to prevent HHV-6 reactivation may concurrently prevent poor reconstitution of CD4+ T cells and aGVHD, thus improving the quality of life and survival of HCT patients. It must be noted, however, that the published clinical studies on the role of HHV-6B in aGVHD are still limited and show an association but not causation. A randomized interventional study would be required to determine causality, although this may prove to be challenging due to the myelosuppressive side effects of current anti-HHV-6 therapies. The development of antiviral medications with anti-HHV-6 activity that do not have severe toxicity (especially myelosuppressive) would provide an opportunity to test the hypotheses outlined herein.

Another idea worth considering is the impact of high-dose steroids on HHV-6B reactivation in “refractory” aGVHD (Fig. 2). We know that steroids can reactivate HHV-6 [24, 26, 84–86] and increase the HHV-6 viral load disproportionately compared to that of EBV or CMV [90]. Albeit limited, there is evidence of an association between HHV-6 reactivation and steroid-refractory aGVHD [23, 88]. Thus, further studies are needed to determine whether HHV-6B may be a causal factor for some “steroid-refractory” aGVHD cases.

In conclusion, if HHV-6B reactivation does play a role in the suppression of CD4+ T-cell reconstitution and subsequent aGVHD, early HHV-6 antiviral prophylaxis or preemptive antiviral treatment might prove beneficial in reducing the overall rates of HHV-6 reactivation and aGVHD. Sufficient evidence exists to justify the development of prospective studies to determine the kinetics of CD4+ T-cell restoration with concomitant careful analysis of HHV-6 reactivation in HCT/CBT patients.

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.).

Footnotes

Conflict of interest The authors declare that they have no conflict of interest.

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