Reactivation of a transplant recipient’s iciHHV-6B resulted in an active infection of his donated liver

Thorough investigation highlights the potential pathological impact of iciHHV-6B in transplantation

Investigators from the University of Helsinki used highly sophisticated techniques to establish that the donor’s integrated virus reactivated and then infected the graft. The authors describe the case of a two-year-old ciHHV-6B+ patient with biliary artresia who received a liver transplant. The graft failed with signs of infection, but no signs of rejection. Ganciclovir treatment was started two weeks post-transplant but a biopsy showed areas of micronecrosis, severe portal fibrosis and cholestasis. A second graft was transplanted successfully, with ganciclovir started immediately after surgery.

While HHV-6 is documented to cause significant morbidity and mortality in transplant cases, little is known about the clinical impact of inherited HHV-6 in transplantation. Traditional PCR-based testing cannot differentiate between transcriptionally silent iciHHV-6 and replicating virus, and standard laboratory tests cannot determine if the virus comes from the donor or the recipient. In this case, the DNA load in the transplanted liver was at a low level (3.1 log10) before the implantation and rose to >6.0 log10 copies after the transplant.

To understand the role of HHV-6 reactivation, and whether it came from the patient’s own integrated strain, the investigators did an extensive study that included:

  • hybrid capture sequencing with targeted enrichment of viral DNA to confirm that the HHV-6B sequences of the donated liver before transplantation differed from the sequences after transplantation.
  • Identification of HHV-6 mRNA transcripts within hepatocytes and biliary cells via reverse transcription PCR and in situ RNA hybridization
  • immunohistochemistry and immunofluorescence, which detected HHV-6 protein expression in the biopsy specimens
  • comparison of the relative abundance of mitochondrial DNA (mtDNA) to confirm that the HHV-6 DNA in the liver didn’t represent infiltration of the recipient’s iciHHV6B cells. (The mtDNA sequences from the liver matched the donor exclusively.)
  • Host genes associated with viral infection were measured, and were persistently elevated

Three cases of iciHHV-6A reactivation in immunocompromised individuals have been described previously (Bonnafous 2018, Endo 2014, Petit 2020).

The pathology documented in this case was similar to that found by French investigators who looked at frozen liver samples from 26 patients with graft hepatitis, and found that high levels of HHV-6 DNA corresponded with confluent periportal necrosis (Buyse 2013).

A commentary in the same publication by experts on iciHHV6 at the University of Washington (Heldman 2024) called the study “a remarkable scientific achievement in virology and transplantation” using methods that are “a giant step forward in sensing the source of HHV-6”. They also noted that although the findings are highly suggestive that reactivated iciHHV-6B played a role, the graft failure may have been due to other factors.

Read the full text: Hannolainen 2024