Summary auto-generated
This study demonstrates that human herpesvirus 6 (HHV-6) can reactivate during in vitro expansion of CD34+ hematopoietic stem cells. Researchers cultured CD34+ cells from 11 peripheral blood progenitor cell samples in serum-free liquid medium supplemented with multiple cytokines (IL-1, IL-3, IL-6, GM-CSF, G-CSF, and SCF) to promote myeloid differentiation over 14-21 days. Among 10 HHV-6-seropositive patients, five showed detection of late, alternatively spliced U100 viral mRNA after 14 or 21 days of culture. One culture yielded infectious virus with an 18-fold increase in viral load by day 21, confirming active viral replication. Previous attempts to induce HHV-6 reactivation in semi-solid cultures had failed, but liquid medium conditions appeared to favor virus replication. The findings suggest that cytokines used for stem cell expansion may activate HHV-6 immediate-early gene transcription, though the exact reactivation mechanisms remain unclear. This research is significant for understanding potential complications during autologous or allogeneic stem cell transplantation, where HHV-6 reactivation could contribute to cytopenias and other clinical complications.
Key findings
- HHV-6 reactivation occurs naturally during ex vivo expansion of CD34+ hematopoietic stem cells in liquid culture medium with multiple cytokines, without exogenous superinfection.
- Half of cultures from HHV-6-seropositive patients (5 of 10) expressed late spliced HHV-6 U100 mRNA indicating complete viral replication cycle, with infectious virus recovered from one expansion.
- HHV-6 DNA was present latently in CD34+ cells but became detectable only during hematopoietic differentiation when viral load increased substantially (18-fold increase observed).
- The reactivation may be triggered by cytokines used for stem cell expansion, particularly those promoting myeloid differentiation toward monocytes and macrophages, which are highly permissive for HHV-6 replication.
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Abstract
Human herpesvirus 6 (HHV-6) replication was evaluated during in vitro expansion of CD34-positive cells that were selected from 11 peripheral blood progenitor cell (PBPC) samples. In order to permit cellular differentiation towards the myeloid lineage, PBPCs were cultured for 1421 days in a liquid, serum-free medium supplemented with interleukin 1 (IL1), IL3, IL6, granulocytemacrophage colony-stimulating factor, granulocyte colony-stimulating factor and stem-cell factor. Among the 10 cultures from HHV-6-seropositive patients, the late, alternatively spliced U100 viral mRNA was detected in five of them after PBPC culture for 14 or 21 days. Recovery of infectious virus from one of the expansions, associated with an increase of HHV-6 viral load and detection of the U100 spliced messenger, confirmed the occurrence of a complete replicative cycle. These data thus demonstrate for the first time that haematopoietic differentiation can lead to HHV-6 reactivation.