Enhancement of Antigen Presentation by Deletion of Viral Immune Evasion Genes Prevents Lethal Cytomegalovirus Disease in Minor Histocompatibility Antigen-Mismatched Hematopoietic Cell Transplantation

Abstract

Hematoablative treatment followed by hematopoietic cell transplantation (HCT) for reconstituting the co-ablated immune system is a therapeutic option to cure aggressive forms of hematopoietic malignancies. In cases of family donors or unrelated donors, immunogenetic mismatches in major histocompatibility complex (MHC) and/or minor histocompatibility (minor-H) loci are unavoidable and bear a risk of graft-vs.-host reaction and disease (GvHR/D). Transient immunodeficiency inherent to the HCT protocol favors a productive reactivation of latent cytomegalovirus (CMV) that can result in multiple-organ CMV disease. In addition, there exists evidence from a mouse model of MHC class-I-mismatched GvH-HCT to propose that mismatches interfere with an efficient reconstitution of antiviral immunity. Here we used a mouse model of MHC-matched HCT with C57BL/6 donors and MHC-congenic BALB.B recipients that only differ in polymorphic autosomal background genes, including minor-H loci coding for minor-H antigens (minor-HAg). Minor-HAg mismatch is found to promote lethal CMV disease in absence of a detectable GvH response to an immunodominant minor-HAg, the H60 locus-encoded antigenic peptide LYL8. Lethality of infection correlates with inefficient reconstitution of viral epitope-specific CD8 + T cells. Notably, lethality is prevented and control of cytopathogenic infection is restored when viral antigen presentation is enhanced by deletion of immune evasion genes from the infecting virus. We hypothesize that any kind of mismatch in GvH-HCT can induce "non-cognate transplantation tolerance" that dampens not only a mismatch-specific GvH response, which is beneficial, but adversely affects also responses to mismatch-unrelated antigens, such as CMV antigens in the specific case, with the consequence of lethal CMV disease.

Insufficient Antigen Presentation Due to Viral Immune Evasion Explains Lethal Cytomegalovirus Organ Disease After Allogeneic Hematopoietic Cell Transplantation

“…This advantage, however, might also be seen as a limitation, because mismatch by gene deletion has no obvious correlate in clinical HCT. As we show in an alternative model of GvH-HCT with a donor (C57BL/6; H-2 b ) vs. recipient (BALB.B; H-2 b ) match in MHC antigens but mismatch in minor histocompatibility antigens (minor-HAg), GvH-associated lethality of mCMV infection and its prevention by enhanced viral antigen presentation can be reproduced (Gezinir et al, 2020).…”

Stochastic Episodes of Latent Cytomegalovirus Transcription Drive CD8 T-Cell “Memory Inflation” and Avoid Immune Evasion

“…For quite some time, this correct finding was mistaken as an evidence against an in vivo relevance of immune evasion in general, although soon thereafter a crucial role of immune evasion in the effector phase of the antiviral CD8 + T-cell response was demonstrated in many models (for a review, see (104)). Recently, it has been shown that immune evasion is the reason for a failure in preventing lethal virus spread and histopathology in mouse models of allogeneic HCT and CMV infection (105,106).…”

Viral G Protein–Coupled Receptors: Attractive Targets for Herpesvirus-Associated Diseases

“…Deletion of Rat CMV R33 reduced vascular sclerosis and increased time to chronic rejection in a rat model of heart transplantation, and deletion of MCMV M33 reduced cardiac allograft vasculopathy in a mouse model of aortic transplantation (Streblow et al, 2005;Fritz et al, 2018). These animal models continue to be developed, including the generation of a humanized mice model, which may soon lead to further exciting insight about the roles of individual viral genes in post-transplant cytomegalovirus disease (Streblow et al, 2015;Crawford et al, 2020;Gezinir et al, 2020;Holtappels et al, 2020;Shah et al, 2020). However, the species-specific nature of herpesviruses will continue to create challenges in understanding how vGPCRs function in vivo.…”