Abstract
Successful reconstitution of cytomegalovirus (CMV)-specific CD8+ T cells by hematopoietic cell transplantation (HCT) gives a favorable prognosis for the control of CMV reactivation and prevention of CMV disease after hematoablative therapy of hematopoietic malignancies. In the transient immunocompromised state after HCT, pre-emptive cytoimmunotherapy with viral epitope-specific effector or memory CD8+ T cells is a promising option to speed up antiviral control. Despite high-coding capacity of CMVs and a broad CD8+ T-cell response on the population level, which reflects polymorphism in major histocompatibility complex class-I (MHC-I) glycoproteins, the response in terms of quantity of CD8+ T cells in any individual is directed against a limited set of CMV-encoded epitopes selected for presentation by the private repertoire of MHC-I molecules. Such epitopes are known as “immunodominant” epitopes (IDEs). Besides host immunogenetics, genetic variance in CMV strains harbored as latent viruses by an individual HCT recipient can also determine the set of IDEs, which complicates a “personalized immunotherapy.” It is, therefore, an important question if IDE-specific CD8+ T-cell reconstitution after HCT is critical or dispensable for antiviral control. As viruses with targeted mutations of IDEs cannot be experimentally tested in HCT patients, we employed the well-established mouse model of HCT. Notably, control of murine CMV (mCMV) after HCT was comparably efficient for IDE-deletion mutant mCMV-Δ4IDE and the corresponding IDE-expressing revertant virus mCMV-Δ4IDE-rev. Thus, antigenicity-loss mutations in IDEs do not result in loss-of-function of a polyclonal CD8+ T-cell population. Although IDE deletion was not associated with global changes in the response to non-IDE epitopes, the collective of non-IDE-specific CD8+ T-cells infiltrates infected tissue and confines infection within nodular inflammatory foci. We conclude from the model, and predict also for human CMV, that there is no need to exclusively aim for IDE-specific immunoreconstitution.
Highlights
Reactivation of human cytomegalovirus, the prototype member of the β-subfamily of herpesviruses, continues to be a medical challenge in recipients of solid organ transplantation (SOT) as well as in the therapy of hematopoietic malignancies by hematoablative treatment followed by hematopoietic cell transplantation (HCT) for reconstitution
Frequencies of cells responding in the enzymelinked immunospot (ELISpot) assay and the corresponding 95% confidence intervals were calculated by intercept-free linear regression analysis from the linear portions of regression lines based on spot counts from triplicate assay cultures for each of the graded cell numbers seeded
The mouse model of CMV infection [reviewed in Ref. [34]] has proven its validity for approaching medical questions that cannot be addressed in patients and that are logistically too demanding to be readily approached in non-human primate models [for reviews, see Ref. [6, 102]]
Summary
Reactivation of human cytomegalovirus (hCMV), the prototype member of the β-subfamily of herpesviruses, continues to be a medical challenge in recipients of solid organ transplantation (SOT) as well as in the therapy of hematopoietic malignancies by hematoablative treatment followed by hematopoietic cell transplantation (HCT) for reconstitution. In both cases, latent CMV is released from immune surveillance by a therapy-inherent immunosuppressive regimen, host-versus-graft reaction (graft rejection) prophylaxis in SOT, and hematoablative treatment as well as graft-versus-host disease prophylaxis in HCT. Liver sinusoidal endothelial cells (LSECs) proved to be a cellular site of mCMV latency and reactivation [22], and in explants of latently infected lung tissue, virus reactivation failed to colocalize with CD11b+ and CX3CR1+ cells of the hematopoietic myeloid differentiation lineage [23]
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