Impact of CMV reactivation, treatment approaches, and immune reconstitution in a nonmyeloablative tolerance induction protocol in cynomolgus macaques

Paula Alonso-Guallart, Raimon Duran-Struuck, Jonah S. Zitsman, Stephen Sameroff, Marcus Pereira, Jeffrey Stern, Erik Berglund, Nathaly Llore, Genevieve Pierre, Emily Lopes, Sigal B. Kofman, Makenzie Danton, Hugo P. Sondermeijer, David Woodland, Yojiro Kato, Dilrukshi K. Ekanayake-Alper, Alina C. Iuga, Cheng Shie Wuu, Anette Wu, W. Ian LipkinRafal Tokarz, Megan Sykes, Adam Griesemer

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Background. Cytomegalovirus (CMV) infection is a serious complication in immunosuppressed patients, specifically transplant recipients. Here, we describe the development and use of an assay to monitor the incidence and treatment of CMV viremia in a Cynomolgus macaque model of bone marrow transplantation (BMT) for tolerance induction. We address the correlation between the course of viremia and immune reconstitution. Methods. Twenty-one animals received a nonmyeloablative conditioning regimen. Seven received cyclosporine A for 28 days and 14 received rapamycin. A CMV polymerase chain reaction assay was developed and run twice per week to monitor viremia. Nineteen recipients were CMV seropositive before BMT. Immune reconstitution was monitored through flow cytometry and CMV viremia was tracked via quantitative polymerase chain reaction. Results. Recipients developed CMV viremia during the first month post-BMT. Two animals developed uncontrollable CMV disease. CMV reactivation occurred earlier in cyclosporine A-treated animals compared with those receiving rapamycin. Post-BMT, T-cell counts remained significantly lower compared with pretransplant levels until CMV reactivation, at which point they increased during the viremic phase and approached pretransplant levels 3 months post-BMT. Management of CMV required treatment before viremia reached 10 000 copies/mL; otherwise clinical symptoms were observed. High doses of ganciclovir resolved the viremia, which could subsequently be controlled with valganciclovir. Conclusions. We developed an assay to monitor CMV in Cynomolgus macaques. CMV reactivation occurred in 100% of seropositive animals in this model. Rapamycin delayed CMV reactivation and ganciclovir treatment was effective at high doses. As in humans, CD8+ T cells proliferated during CMV viremia.

Original languageEnglish (US)
Pages (from-to)270-279
Number of pages10
JournalTransplantation
DOIs
StateAccepted/In press - 2020
Externally publishedYes

ASJC Scopus subject areas

  • Transplantation

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