Abstract
Background: Reactivation of latent human cytomegalovirus (CMV) in patients undergoing allogeneic stem-cell transplantation (HSCT) predisposes to several clinical complications and is therefore a major cause of morbidity and mortality. Although pentraxin-3 (PTX3) has been previously described to bind both human and murine CMV and mediate several host antiviral mechanisms, whether genetic variation in the PTX3 locus influences the risk of CMV infection is currently unknown.Methods: To dissect the contribution of genetic variation within PTX3 to the development of CMV infection, we analyzed described loss-of-function variants at the PTX3 locus in 394 recipients of HSCT and their corresponding donors and assessed the associated risk of CMV reactivation.Results: We report that the donor, but not recipient, h2/h2 haplotype in PTX3 increased the risk of CMV reactivation after 24 months following transplantation, with a significant effect on survival. Among recipients with h2/h2 donors, CMV seropositive patients as well as those receiving grafts from unrelated donors, regardless of the CMV serostatus, were more prone to develop viral reactivation after transplantation. Most importantly, the h2/h2 haplotype was demonstrated to display an influence toward risk of CMV reactivation comparable to that conferred by the unrelated status of the donor alone.Conclusions: Our findings demonstrate the important contribution of genetic variation in donor PTX3 to the risk of CMV reactivation in patients undergoing HSCT, highlighting a promising prognostic value of donor PTX3 to predict risk of CMV reactivation in this clinical setting.
Highlights
Human cytomegalovirus (CMV), a member of the Herpesviridae family, is a ubiquitous opportunistic pathogen that has intimately co-evolved with its human host and can establish latency after clearance of the primary infection [1]
No significant differences were observed among cases of CMV reactivation and control groups regarding the age at transplantation, gender, underlying hematological disease, graft source, disease stage at transplantation, conditioning regimen, development of acute graft-vs.-host disease (GVHD) and duration of neutropenia
An increased number of cases of CMV infection was detected among serologically positive recipients (R+), whereas recipients with negative CMV serostatus (R–) were instead more protected from viral reactivation (P < 0.0001)
Summary
Human cytomegalovirus (CMV), a member of the Herpesviridae family, is a ubiquitous opportunistic pathogen that has intimately co-evolved with its human host and can establish latency after clearance of the primary infection [1]. Throughout complex virus-host interactions, CMV evades a number of host pathways to enable its lifelong persistence, during which it may replicate chronically or reactivate from latency sporadically [4]. In immunocompetent individuals, these reactivation events are tightly controlled by the immune system and rarely result in clinical presentation [5]. Reactivation of latent virus following allogeneic hematopoietic stem-cell transplantation (HSCT) has been increasingly associated with overt CMV disease, a major cause of morbidity and mortality in these patients. Reactivation of latent human cytomegalovirus (CMV) in patients undergoing allogeneic stem-cell transplantation (HSCT) predisposes to several clinical complications and is a major cause of morbidity and mortality. Pentraxin-3 (PTX3) has been previously described to bind both human and murine CMV and mediate several host antiviral mechanisms, whether genetic variation in the PTX3 locus influences the risk of CMV infection is currently unknown
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