Abstract
Human cytomegalovirus (HCMV) is a widespread pathogen establishing a latent infection in its host. HCMV reactivation is a major health burden in immunocompromised individuals, and is a major cause of morbidity and mortality following hematopoietic stem cell transplantation (HSCT). Here we determined HCMV genomic levels using droplet digital PCR in different peripheral blood mononuclear cell (PBMC) populations in HCMV reactivating HSCT patients. This high sensitivity approach revealed that all PBMC populations harbored extremely low levels of viral DNA at the peak of HCMV DNAemia. Transcriptomic analysis of PBMCs from high-DNAemia samples revealed elevated expression of genes typical of HCMV specific T cells, while regulatory T cell enhancers as well as additional genes related to immune response were downregulated. Viral transcript levels in these samples were extremely low, but remarkably, the detected transcripts were mainly immediate early viral genes. Overall, our data indicate that HCMV DNAemia is associated with distinct signatures of immune response in the blood compartment, however it is not necessarily accompanied by substantial infection of PBMCs and the residual infected PBMCs are not productively infected.
Highlights
Human cytomegalovirus (HCMV) is a widespread pathogen infecting most of the population worldwide
Following hematopoietic stem cell transplantation (HSCT), patients are monitored for HCMV reactivation by means of measuring viral DNA loads either in whole blood or in plasma, it is unclear what is the source of the detected viral DNA and which cells in the blood carry HCMV
Twenty-four hours post infection, cells were FACS sorted based on standard cell markers to distinct blood cell types: CD14+CD16- cells which are mainly classical monocytes, CD16+CD14- cells which include nonclassical monocytes (Guilliams et al, 2018), a subset of NK cells (Lanier et al, 1989), and dendritic cells (Fromm et al, 2020), and T and B cells according to cell surface markers CD3 and CD19, respectively (Figure 1A)
Summary
Human cytomegalovirus (HCMV) is a widespread pathogen infecting most of the population worldwide. For hematopoietic stem cell transplantation (HSCT) patients HCMV. HCMV Reactivation in HSCT Patients reactivation is a major risk factor (Stern et al, 2019). Reactivation in these patients can lead to HCMV disease that manifests in diverse symptoms, from gastroenteritis to respiratory symptoms, hepatitis and retinitis, and is associated with graft versus host disease (Cantoni et al, 2010; Ljungman et al, 2017). Pre-transplant HCMV serostatus of the donor and recipient is the major risk factor for HCMV reactivation and disease following HSCT, with HCMV seropositivity of the recipient conferring the highest risk (George et al, 2010; Webb et al, 2018). HCMV reactivation develops in more than 50% of the cases where the recipient was HCMV seropositive and the donor was seronegative (R+/D-), while in cases where the recipient was HCMV seronegative and the donor was HCMV seropositive (R-/ D+) there is a ~10% risk
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