CD4+ T cells are the major predictor of HCMV control in allogeneic stem cell transplant recipients on letermovir prophylaxis

Frontiers in Immunology

Immunology

Sebastian Wurster¹  Carolin Köchel²  Chris David Lauruschkat²  Denise Grathwohl²  Alice Rein²  Hermann Einsele²  Sabrina Kraus²  Götz Ulrich Grigoleit³  Christine Susanne Falk⁴  Ihsan Muchsin⁵  Florian Erhard⁵  Lars Dölken⁶ 

[1] Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, TX, United States;Department of Internal Medicine II, University Hospital of Wuerzburg, Wuerzburg, Germany;Department of Internal Medicine II, University Hospital of Wuerzburg, Wuerzburg, Germany;Department of Hematology, Oncology and Immunology, Helios Hospital Duisburg, Duisburg, Germany;Hannover Medical School, Institute of Transplant Immunology, Hanover, Germany;TTU-IICH, German Center for Infection Research (DZIF), Hannover-Braunschweig, Germany;BREATH Site, German Center for Lung Research (DZL), Hannover-Braunschweig, Germany;Institute for Virology and Immunobiology, Julius-Maximilians-University Wuerzburg, Wuerzburg, Germany;Institute for Virology and Immunobiology, Julius-Maximilians-University Wuerzburg, Wuerzburg, Germany;Helmholtz-Institute for RNA-based Infection Research (HIRI), Helmholtz-Center for Infection Research (HZI), Wuerzburg, Germany;

关键词: human cytomegalovirus (HCMV);    viral infection;    allogeneic stem cell transplantation;    T cells;    NK cells;   

DOI  :  10.3389/fimmu.2023.1148841

 received in 2023-01-20, accepted in 2023-04-20,  发布年份 2023

来源: Frontiers

【 摘 要 】

IntroductionHuman cytomegalovirus (HCMV) causes significant morbidity and mortality in allogeneic stem cell transplant (alloSCT) recipients. Recently, antiviral letermovir prophylaxis during the first 100 days after alloSCT replaced PCR-guided preemptive therapy as the primary standard of care for HCMV reactivations. Here, we compared NK-cell and T-cell reconstitution in alloSCT recipients receiving preemptive therapy or letermovir prophylaxis in order to identify potential biomarkers predicting prolonged and symptomatic HCMV reactivation.MethodsTo that end, the NK-cell and T-cell repertoire of alloSCT recipients managed with preemptive therapy (n=32) or letermovir prophylaxis (n=24) was characterized by flow cytometry on days +30, +60, +90 and +120 after alloSCT. Additionally, background-corrected HCMV-specific T-helper (CD4+IFNγ+) and cytotoxic (CD8+IFNγ+CD107a+) T cells were quantified after pp65 stimulation.ResultsCompared to preemptive therapy, letermovir prophylaxis prevented HCMV reactivation and decreased HCMV peak viral loads until days +120 and +365. Letermovir prophylaxis resulted in decreased T-cell numbers but increased NK-cell numbers. Interestingly, despite the inhibition of HCMV, we found high numbers of “memory-like” (CD56dimFcεRIγ- and/or CD159c+) NK cells and an expansion of HCMV-specific CD4+ and CD8+ T cells in letermovir recipients. We further compared immunological readouts in patients on letermovir prophylaxis with non/short-term HCMV reactivation (NSTR) and prolonged/symptomatic HCMV reactivation (long-term HCMV reactivation, LTR). Median HCMV-specific CD4+ T-cell frequencies were significantly higher in NSTR patients (day +60, 0.35 % vs. 0.00 % CD4+IFNγ+/CD4+ cells, p=0.018) than in patients with LTR, whereas patients with LTR had significantly higher median regulatory T-cell (Treg) frequencies (day +90, 2.2 % vs. 6.2 % CD4+CD25+CD127dim/CD4+ cells, p=0.019). ROC analysis confirmed low HCMV specific CD4+ (AUC on day +60: 0.813, p=0.019) and high Treg frequencies (AUC on day +90: 0.847, p=0.021) as significant predictors of prolonged and symptomatic HCMV reactivation.DiscussionTaken together, letermovir prophylaxis delays HCMV reactivation and alters NK- and T-cell reconstitution. High numbers of HCMV-specific CD4+ T cells and low numbers of Tregs seem to be pivotal to suppress post-alloSCT HCMV reactivation during letermovir prophylaxis. Administration of more advanced immunoassays that include Treg signature cytokines might contribute to the identification of patients at high-risk for long-term and symptomatic HCMV reactivation who might benefit from prolonged administration of letermovir.

【 授权许可】

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Copyright © 2023 Lauruschkat, Muchsin, Rein, Erhard, Grathwohl, Dölken, Köchel, Falk, Einsele, Wurster, Grigoleit and Kraus