The Cell Biology of Cytomegalovirus: Implications for Transplantation

Abstract

Interpretation of clinical data regarding the impact of cytomegalovirus (CMV) infection on allograft function is complicated by the diversity of viral strains and substantial variability of cellular receptors and viral gene expression in different tissues. Variation also exists in nonspecific (monocytes and dendritic cells) and specific (NK cells, antibodies) responses that augment T cell antiviral activities. Innate immune signaling pathways and expanded pools of memory NK cells and cd T cells also serve to amplify host responses to infection. The clinical impact of specific memory T cell anti-CMV responses that cross-react with graft antigens and alloantigens is uncertain but appears to contribute to graft injury and to the abrogation of allograft tolerance. These responses are modified by diverse immunosuppressive regimens and by underlying host immune deficits. The impact of CMV infection on the transplant recipient reflects cellular changes and corresponding host responses, the convergence of which has been termed the "indirect effects" of CMV infection. Future studies will clarify interactions between CMV infection and allograft injury and will guide interventions that may enhance clinical outcomes in transplantation.

Impact of donor and recipient cytomegalovirus serology on long‐term survival of lung transplant recipients

“…Over the past 20 years, improved cytomegalovirus (CMV) molecular diagnostics, prevention and treatment has had a significant impact on direct morbidity and mortality associated with CMV disease after solid organ transplantation . CMV infection in the transplant setting is associated with both significant immunomodulation and inflammation and may induce allogeneic immune responses to the allograft effects that have been described as indirect effects . These indirect effects have been hypothesized to impact both graft and patient survival.…”

Absence of interaction between porcine endogenous retrovirus and porcine cytomegalovirus in pig‐to‐baboon renal xenotransplantation in vivo

“…This may reflect either specific or non‐specific stimulation of MHC transcription by infection. CMV infection in vivo tends to provoke allograft rejection as well as xenograft rejection, possibly via T‐cell priming and endothelial activation . Similar variation was not observed for GAPDH amplification, and therefore, the ratio of PERV pol expression to GAPDH ratio serves as a useful control for input cellular nucleic acids.…”

“…Despite these observations, as PERV receptors are defective in non‐human primates, clinical infectious risk cannot be readily assessed in this model. Interestingly, the selection of internal controls for amplification reactions was critical given that MHC expression was increased by over 3‐fold in the animals with PCMV infection and could not be used as an internal reaction control for these studies . This may reflect either specific or non‐specific stimulation of MHC transcription by infection.…”

“…Porcine cytomegalovirus is largely species‐specific with infection restricted to the xenograft in pig‐to‐baboon transplants . PCMV infection causes endothelial activation in cultured cells in vitro and in pig vessels in vivo with increased expression of ICAM‐1, vascular thrombosis, disseminated intravascular coagulation, and neutropenia; as a result, PCMV infection increases graft rejection and reduces the survival of porcine xenografts in baboon recipients . PCMV is susceptible to antiviral agents in vitro including ganciclovir .…”

Going beyond serology for stratifying the risk of CMV infection in transplant recipients

“…Hereafter, specific clinical and immunological variables that influence the susceptibility to CMV infection in the setting of SOT and allo‐HSCT will be separately reviewed in each of the sections. SOT setting : CMV is efficiently transmitted through organ transplantation, and such risk increases in the absence of preexisting CMV‐specific immunity in the recipient and with the amount of lymphoid tissue in the graft . In addition, the long‐term immunosuppression required to prevent graft rejection poses an additional risk of CMV reactivation among seropositive recipients (R + ) with previously acquired latent infection .…”