Potential Beneficial Effects of Cytomegalovirus Infection after Transplantation

Abstract

Cytomegalovirus (CMV) infection can cause significant complications after transplantation, but recent emerging data suggest that CMV may paradoxically also exert beneficial effects in two specific allogeneic transplant settings. These potential benefits have been underappreciated and are therefore highlighted in this review. First, after allogeneic hematopoietic stem cell transplantation (HSCT) for acute myeloid leukemia (AML) using T-cell and natural killer (NK) cell-replete grafts, CMV reactivation is associated with protection from leukemic relapse. This association was not observed for other hematologic malignancies. This anti-leukemic effect might be mediated by CMV-driven expansion of donor-derived memory-like NKG2C+ NK and Vδ2negγδ T-cells. Donor-derived NK cells probably recognize recipient leukemic blasts by engagement of NKG2C with HLA-E and/or by the lack of donor (self) HLA molecules. Vδ2negγδ T cells probably recognize as yet unidentified antigens on leukemic blasts via their TCR. Second, immunological imprints of CMV infection, such as expanded numbers of Vδ2negγδ T cells and terminally differentiated TCRαβ+ T cells, as well as enhanced NKG2C gene expression in peripheral blood of operationally tolerant liver transplant patients, suggest that CMV infection or reactivation may be associated with liver graft acceptance. Mechanistically, poor alloreactivity of CMV-induced terminally differentiated TCRαβ+ T cells and CMV-induced IFN-driven adaptive immune resistance mechanisms in liver grafts may be involved. In conclusion, direct associations indicate that CMV reactivation may protect against AML relapse after allogeneic HSCT, and indirect associations suggest that CMV infection may promote allograft acceptance after liver transplantation. The causative mechanisms need further investigations, but are probably related to the profound and sustained imprint of CMV infection on the immune system.

Co-infections of human herpesviruses (CMV, HHV-6, HHV-7 and EBV) in non-transplant acute leukemia patients undergoing chemotherapy

“…However, paradoxical recent data suggest that CMV replication may protect against AML relapse after allo-HSCT [32]. Whether CMV reactivation can protect against relapse after allo-HSCT for other hematological malignancies patients is controversial [33,34]. More research is further needed to better understand these enigmatic observations.…”

Herpesviruses: Harmonious Pathogens but Relevant Cofactors in Other Diseases?

“…Recent studies have shown that herpesviruses may, in fact, help fine-tune host immunity. This occurs by modulating one or more types of immune responses to make the host either more resistant or susceptible to other disease situations (Barton et al, 2007 ; White et al, 2010 ; Furman et al, 2015 ; Litjens et al, 2018 ) For example, some studies measured the influence of persisting β-herpesvirus (MCMV) or a γ-herpesvirus (MHV68) infection on the subsequent infection by Listeria monocytogenes and Yersinia pestis . Previously infected mice controlled these infections better than those not infected with MHV68 (Barton et al, 2007 ).…”

“…Depending on the herpesvirus involved, the outcome of transplantation procedures might vary. For example, HSCT aimed at improving the prognosis of acute myeloid leukemia (AML), induced reactivation of CMV which then expanded a subset of donor derived NKG2C expressing NK cells as well as γδ-T cells of a particular phenotype (Vδ2 −ve γδ-T cells) (Litjens et al, 2018 ). These cells helped control the relapse of leukemic episodes thereby benefiting the host.…”

“…The general perception is that herpesviruses are innocuous pathogens, a status that can probably be attributed to their long association with mankind (Parrish et al, 2008 ). In some instances, the persisting herpesvirus infections might even provide some benefits to the host against other infections and clinical conditions such as malignancies (Barton et al, 2007 ; White et al, 2012 ; Furman et al, 2015 ; Litjens et al, 2018 ). Humans not infected with any of the herpesviruses however, represent a rare subset; therefore in comparison to infected individuals their ability to handle other infections is not well-established.…”

Viral ecosystem: An epidemiological hypothesis

“…Chronic infection with CMV and the hidden presence of this virus in the body of patients with leukemia and lymphoma have been shown to produce specific natural killer (NK) cells . After bone marrow transplantation, these specific immune cells, by inhibiting the remaining cancerous cells, have prevent the recurrence of leukemia and even reduce the development of graft versus host disease (GVHD) . A study showed that prolonged CMV protects its host against bacterial infection, which has been proven in the rat model.…”