Immune control of cytomegalovirus reactivation in stem cell transplantation

Abstract

The reactivation of viruses from latency after allogeneic stem cell transplantation (SCT) continues to represent a major clinical challenge requiring sophisticated monitoring strategies in the context of prophylactic and/or pre-emptive antiviral drugs that are associated with significant expense, toxicity, and rates of failure. Accumulating evidence has demonstrated the association of polyfunctional virus-specific T-cells with protection from viral reactivation, affirmed by the ability of adoptively transferred virus-specific T-cells to prevent and treat reactivation and disease. The roles of innate cells (NK cells) in early viral surveillance, and dendritic cells in priming of T-cells have also been delineated. Most recently, a role for strain-specific humoral responses in preventing early cytomegalovirus (CMV) reactivation has been demonstrated in preclinical models. Despite these advances, many unknowns remain: what are the critical innate and adaptive responses over time, is the origin (e.g. recipient versus donor) and localization (e.g. in parenchymal tissue versus lymphoid organs) of these responses important, how does GVHD and the prevention/treatment thereof (e.g. high dose steroids) impact the functionality and relevance of a particular immune axis, do the immune parameters that control latency, reactivation and dissemination differ, and what is the impact of new antiviral drugs on the development of enduring antiviral immunity. Thus, whilst antiviral drugs have provided major improvements over the last two decades, understanding the immunological paradigms underpinning protective antiviral immunity after SCT offers the potential to generate non-toxic immune-based therapeutic approaches for lasting protection from viral reactivation.