Human herpesvirus 6–specific T-cell immunity in allogeneic hematopoietic stem cell transplant recipients

Human Herpesvirus-6 (HHV-6) can reactivate after allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT), and may lead to severe symptoms. HHV-6-specific immune responses after HSCT are largely unexplored. We conducted a prospective observational study on 208 consecutive adult patients who received allo-HSCT, to investigate HHV-6 reactivations and specific immune responses. IFN-γ-producing HHV-6-specific T cells were quantified by ELISpot assay. "HHV-6 reactivation" occurred in 63% of patients, at a median of 25 days (range 3-538) from allo-HSCT. Only 40% of these presented a "clinically relevant infection", defined according to center guidelines by the presence of classical HHV-6 End-Organ Diseases (EOD), based on European-Conference-on-Infections-in-Leukaemia (ECIL) guidelines, and other possible HHV6-related EODs. By multivariate analysis, we identified risk factors for HHV-6 reactivation: previous allo-HSCT (Hazard Ratio, HR=2.89; p-value<0.01), post-transplant cyclophosphamide (PT-Cy; HR=2.59; p-value<0.01), time-dependent steroids introduction (HR=3.64; p-value<0.01). The use of PT-Cy (HR=3.77; p-value<0.01) and steroids (HR=2.74; p-value<0.01) were associated with clinically relevant infections, whereas higher CD3+ cell counts (HR=0.23; p-value=0.02) seemed to be protective. Interestingly, circulating HHV-6-specific T cells were significantly higher in reactivating patients. Moreover, HHV-6-specific T-cell responses, quantified at >4 days after the first viremia detection, predicted clinically relevant infections (p-value<0.0001), with higher specificity (93%) and sensitivity (79%) than polyclonal CD3+ cells/μl (<100/µl; specificity=59%; sensitivity=36%). Overall survival and transplant-related mortality were not affected by time-dependent HHV-6 reactivation, while a significant association was observed between clinically relevant infections and acute graft-versus-host disease. These results shed light on the role of HHV-6 in allo-HSCT and may impact on HHV-6 monitoring and treatment.