Reactivation of a Transplant Recipient's Inherited Human Herpesvirus 6 and Implications to the Graft

Abstract Background The implications of inherited chromosomally integrated human herpesvirus 6 (iciHHV-6) in solid organ transplantation remain uncertain. Although this trait has been linked to unfavorable clinical outcomes, an association between viral reactivation and complications has only been conclusively established in a few cases. Methods We used hybrid capture sequencing for in-depth analysis of the viral sequences reconstructed from sequential liver biopsies. Moreover, we investigated viral replication through in situ hybridization (U38–U94 genes), reverse transcriptase polymerase chain reaction (U89/U90 genes), immunohistochemistry, and immunofluorescence. We also performed whole transcriptome sequencing to profile the host immune response. Results We report a case of reactivation of a recipient’s iciHHV-6B and subsequent infection of the graft. Using a novel approach integrating the analysis of viral and mitochondrial DNAs, we located the iciHHV-6B intragraft. We demonstrated active replication via the emergence of viral minor variants, in addition to positive viral messenger RNAs and antigen stainings in tissue sections. Furthermore, we detected significant upregulation of antiviral immune responses, arguing against immunotolerance. Conclusions Our analysis underscores the potential pathological impact of iciHHV-6B, emphasizing the need for monitoring reactivation in transplant recipients. Most crucially, it highlights the critical role that the host's virome can play in shaping the outcome of transplantation.