Abstract
Human cytomegalovirus (HCMV) infection is a serious complication in hematopoietic stem cell transplant (HSCT) recipients due to virus-induced myelosuppression and impairment of stem cell engraftment. Despite the clear clinical link between myelosuppression and HCMV infection, little is known about the mechanism(s) by which the virus inhibits normal hematopoiesis because of the strict species specificity and the lack of surrogate animal models. In this study, we developed a novel humanized mouse model system that recapitulates the HCMV-mediated engraftment failure after hematopoietic cell transplantation. We observed significant alterations in the hematopoietic populations in peripheral lymphoid tissues following engraftment of a subset of HCMV+ CD34+ hematopoietic progenitor cells (HPCs) within the transplant, suggesting that a small proportion of HCMV-infected CD34+ HPCs can profoundly affect HPC differentiation in the bone marrow microenvironment. This model will be instrumental to gain insight into the fundamental mechanisms of HCMV myelosuppression after HSCT and provides a platform to assess novel treatment strategies.
Highlights
Human cytomegalovirus (HCMV) infection after Hematopoietic Stem Cell Transplantation (HSCT) is still a significant cause of morbidity and mortality in the transplant population
We recently published that latent HCMV infection of CD34+ hematopoietic progenitor cells (HPCs) induces the secretion of TGF-β that is responsible for virus-mediated myelosuppression [6]
Even though these results provide relevant insights into the mechanism(s) for how the latent HCMV infection of a minor population of CD34+ HPCs in the bone marrow induces global myelosuppression in HSCT patients, the strict species specificity of HCMV and the lack of surrogate animal models have precluded the in vivo validation of these findings as well as the development of preventive strategies that can target latently infected cells
Summary
Human cytomegalovirus (HCMV) infection after Hematopoietic Stem Cell Transplantation (HSCT) is still a significant cause of morbidity and mortality in the transplant population. Our group has developed the first humanized mouse model in which human CD34+ HPC-engrafted NOD.Cg-PrkdcscidIL2rγtm1Wjl null (huNSG) mice infected with HCMV can support a latent viral infection and where reactivation occurs in human macrophages following G-CSF-induced mobilization of bone-marrow hematopoietic cells [7]. These data recapitulate observations made in hematopoietic stem cell transplant patients receiving G-CSF-mobilized cells from HCMV-seropositive donors [8,9,10] and provide definitive evidence that CD34+ HPCs and monocytes are the source of latent HCMV (reviewed in [11]). We demonstrate evidence of HCMV-mediated engraftment failure after hematopoietic cell transplantation, thereby recapitulating the clinical observations and validating this model as a tool for testing novel therapeutics
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