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

During mouse cytomegalovirus (CMV) infection, a population of Ly49H(+) natural killer (NK) cells expands and is responsible for disease clearance through the induction of a "memory NK-cell response." Whether similar events occur in human CMV infection is unknown. In the present study, we characterized the kinetics of the NK-cell response to CMV reactivation in human recipients after hematopoietic cell transplantation. During acute infection, NKG2C(+) NK cells expanded and were potent producers of IFNγ. NKG2C(+) NK cells predominately expressed killer cell immunoglobulin-like receptor, and self-killer cell immunoglobulin-like receptors were required for robust IFNγ production. During the first year after transplantation, CMV reactivation induced a more mature phenotype characterized by an increase in CD56(dim) NK cells. Strikingly, increased frequencies of NKG2C(+) NK cells persisted and continued to increase in recipients who reactivated CMV, whereas these cells remained at low frequency in recipients without CMV reactivation. Persisting NKG2C(+) NK cells lacked NKG2A, expressed CD158b, preferentially acquired CD57, and were potent producers of IFNγ during the first year after transplantation. Recipients who reactivated CMV also expressed higher amounts of IFNγ, T-bet, and IL-15Rα mRNA transcripts. Our findings support the emerging concept that CMV-induced innate memory-cell populations may contribute to malignant disease relapse protection and infectious disease control long after transplantation.

Cytomegalovirus (CMV) infection does not usually produce symptoms when it causes primary infection, reinfection, or reactivation because these three types of infection are all controlled by the normal immune system. However, CMV becomes an important pathogen in individuals whose immune system is immature or compromised, such as the unborn child. Several vaccines against CMV are currently in clinical trials that aim to induce immunity in seronegative individuals and/or to boost the immunity of those with prior natural infection (seropositives). To facilitate estimation of the burden of disease and the need for vaccines that induce de novo immune responses or that boost pre-existing immunity to CMV, we conducted a systematic survey of the published literature to describe the global seroprevalence of CMV IgG antibodies. We estimated a global CMV seroprevalence of 83% (95%UI: 78-88) in the general population, 86% (95%UI: 83-89) in women of childbearing age, and 86% (95%UI: 82-89) in donors of blood or organs. For each of these three groups, the highest seroprevalence was seen in the World Health Organisation (WHO) Eastern Mediterranean region 90% (95%UI: 85-94) and the lowest in WHO European region 66% (95%UI: 56-74). These estimates of the worldwide CMV distribution will help develop national and regional burden of disease models and inform future vaccine development efforts.

Single-center studies have reported an association between early (before day 100) cytomegalovirus (CMV) reactivation and decreased incidence of relapse for acute myeloid leukemia (AML) following allogeneic hematopoietic cell transplantation. To substantiate these preliminary findings, the Center for International Blood and Marrow Transplant Research (CIBMTR) Database was interrogated to analyze the impact of CMV reactivation on hematologic disease relapse in the current era. Data from 9469 patients transplanted with bone marrow or peripheral blood between 2003 and 2010 were analyzed according to 4 disease categories: AML (n = 5310); acute lymphoblastic leukemia (ALL, n = 1883); chronic myeloid leukemia (CML, n = 1079); and myelodysplastic syndrome (MDS, n = 1197). Median time to initial CMV reactivation was 41 days (range, 1-362 days). CMV reactivation had no preventive effect on hematologic disease relapse irrespective of diagnosis. Moreover, CMV reactivation was associated with higher nonrelapse mortality [relative risk [RR] among disease categories ranged from 1.61 to 1.95 and P values from .0002 to <.0001; 95% confidence interval [CI], 1.14-2.61). As a result, CMV reactivation was associated with lower overall survival for AML (RR = 1.27; 95% CI, 1.17-1.38; P <.0001), ALL (RR = 1.46; 95% CI, 1.25-1.71; P <.0001), CML (RR = 1.49; 95% CI, 1.19-1.88; P = .0005), and MDS (RR = 1.31; 95% CI, 1.09-1.57; P = .003). In conclusion, CMV reactivation continues to remain a risk factor for poor posttransplant outcomes and does not seem to confer protection against hematologic disease relapse.