Human Cytomegalovirus Latency and Reactivation in Allogeneic Hematopoietic Stem Cell Transplant Recipients

Abstract

Human cytomegalovirus (HCMV) reactivation is a major infectious cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). HCMV is a ubiquitous beta-herpesvirus which asymptomatically infects immunocompetent individuals but establishes lifelong latency, with the potential to reactivate to a life-threatening productive infection when the host immune system is suppressed or compromised. Opportunistic HCMV reactivation is the most common viral complication following engraftment after HSCT and is associated with a marked increase in non-relapse mortality, which appears to be linked to complex effects on post-transplant immune recovery. This minireview explores the cellular sites of HCMV latency and reactivation in HSCT recipients and provides an overview of the risk factors for HCMV reactivation post-HSCT. The impact of HCMV in shaping post-transplant immune reconstitution and its relationship with patient outcomes such as relapse and graft-versus-host disease will be discussed. Finally, we survey current and emerging strategies to prevent and control HCMV reactivation in HSCT recipients, with recent developments including adoptive T cell therapies to accelerate HCMV-specific T cell reconstitution and new anti-HCMV drug therapy for HCMV reactivation after HSCT.

Bright and Early: Inhibiting Human Cytomegalovirus by Targeting Major Immediate-Early Gene Expression or Protein Function

“…HCMV replicates in a wide variety of differentiated cell types, and targets select types of poorly differentiated cells including myeloid progenitors for latent infection with limited viral gene expression [22][23][24][25][26]. Viral reactivation from latency is brought about by cellular differentiation and/or stimulation and contributes greatly to pathogenesis in vulnerable hosts [27][28][29].…”

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

“…Among viral complications in HCT patients, infection with human cytomegalovirus (hCMV) is the most frequent and most feared. It can lead to lethal organ disease, in particular to interstitial pneumonia, unless infection is treated by preemptive antiviral chemotherapy as soon as diagnosed in the routine follow-up monitoring (Hebart and Einsele, 2004;Seo and Boeckh, 2013;Stern et al, 2019). As antivirals have adverse off-target effects, including inhibition of hematopoietic reconstitution, adoptive immunotherapy of hCMV infection by immune cell transfer is used in clinical trials as a potentially less burdening alternative (Riddell et al, 1992;Walter et al, 1995;Moss and Rickinson, 2005;Feuchtinger et al, 2010;Neuenhahn et al, 2017).…”

“…Except in rare and rather accidental cases, hCMV infection in HCT recipients is not caused by transmission of infectious virus from a virus-shedding contact person or by an acutely infected transplant. Instead, it results from reactivation of latent virus present in HC of a latently infected donor or, more frequently, of latent virus harbored already pre-HCT in cells of the recipient (Emery, 1998;Stern et al, 2019; for a review and discussion, see Reddehase and Lemmermann, 2019). Notably, the incidence of hCMV organ disease is more frequent in allogeneic HCT with family donors or unrelated donors, compared to syngeneic HCT with identical twins as donor and recipient (Applebaum et al, 1982;Meyers et al, 1982) or to autologous HCT (Wingard et al, 1988).…”

Cytomegalovirus-Associated Inhibition of Hematopoiesis Is Preventable by Cytoimmunotherapy With Antiviral CD8 T Cells

“…The risk of cytomegalovirus (CMV) reactivation and consequent CMV disease remains a severe infectious complication in the treatment of hematopoietic malignancies by hematopoietic cell transplantation (HCT), which is the last therapeutic resort for aggressive leukemias that resist standard therapies. Accordingly, monitoring and management of CMV reactivation in latently infected HCT recipients is a medical task and challenge at transplantation centers worldwide (Seo and Boeckh, 2013;Ljungman et al, , 2019Stern et al, 2019). The aim of HCT is to repopulate the emptied bone marrow (BM) in HCT recipients who have undergone therapy-inherent hematoablative treatment for elimination of the malignant cells.…”