Inherited ciHHV-6 increases risk of developing acute GVHD and CMV in transplant patients

In All, Cancer, ciHHV-6, GVHD by Kristin Loomis

A higher prevalence of inherited virus was found in patients.

Investigators at Fred Hutchinson Cancer Center led by Joshua Hill and Michael Boeckh determined that transplant patients with inherited ciHHV-6 (iciHHV-6) were twice as likely to develop acute graft vs host disease (aGVHD) and three times more likely to develop high level cytomegalovirus (CMV) viremia. However, iciHHV-6 status did not affect overall mortality. Transplant patients were also significantly more likely to have iciHHV-6 than donors.

Cumulative Incidence of acute GVHD according to iciHHV-6 status (Source: Blood, American Society of Hematology)

HHV-6A and HHV-6B have a unique ability to integrate into human chromosomes as a form of latency, and when viral integration occurs in a germline cell, the offspring will be born with a full copy of the HHV-6 genome in every nucleated cell. Although it was originally thought to be a “dead end” form of latency, integrated HHV-6 is now known to generate gene expression and reactivate in response to certain drugs, including steroids, as well as in patients who are immunocompromised (Endo 2014).

The Fred Hutchinson group found that 0.9% of 4,319 donors had the inherited genome, compared to 1.4% of cancer patients receiving a transplant, suggesting that iciHHV-6 status may affect the likelihood of developing cancer.

Early HHV-6 reactivation post-transplantation has been found to increase the risk of aGVHD in multiple studies (Cirrone 2016Verhoeven 2015Gotoh 2014De Pagter 2013, Zerr 2012), and several studies have shown that HHV-6B reactivation increases the risk of CMV reactivation – by 15X in one study (Crocchiolo 2016). This is the first study to demonstrate that inherited ciHHV-6 is also associated with aGVHD and a higher risk of CMV reactivation.

In multivariable Cox proportional hazards models, the adjusted hazard ratio for aGVHD in patients with iciHHV-6 or with iciHHV-6 donor cells was 1.7 and 1.9 respectively (p=0.004 and p<0.001). Patients with iciHHV-6 had were more likely to develop both low level cytomegalovirus viremia as well as high level infections (HR of 1.7 and 3.1; p= 0.001- 0.040). HHV-6B was found in 71% of ciHHV-6+ individuals compared to 29% with HHV-6A. The adverse consequences of iciHHV-6 status were similar whether the donor or recipient was positive for iciHHV-6. A small number of the donor-recipient pairs were both positive for iciHHV-6, but these were mostly related family members, making a comparison to unrelated pairs more difficult.

The authors recommend that screening for inherited ciHHV-6 should be considered to guide donor selection, risk stratification, and treatment strategies after transplantation. “Further study is required”, notes first author Joshua Hill, “to replicate these findings and to understand the direct or indirect mechanisms by which inherited ciHHV-6 may lead to the associations demonstrated in this study.”

Read the full paper: Hill 2017b