Impaired T cells and “memory-like” NK-cell reconstitution is linked to late-onset HCMV reactivation after letermovir cessation

• Published in: Blood advances 2024-06, Vol.8 (11), p.2967-2979
• Main Authors: Lauruschkat, Chris David, Muchsin, Ihsan, Rein, Alice Felicitas, Erhard, Florian, Grathwohl, Denise, Dölken, Lars, Köchel, Carolin, Nehmer, Anne, Falk, Christine Susanne, Grigoleit, Götz Ulrich, Einsele, Hermann, Wurster, Sebastian, Kraus, Sabrina
• Format: Article
• Language: English
• Subjects: Acetates - pharmacology; Acetates - therapeutic use; Adult; Aged; Antiviral Agents - therapeutic use; Cytomegalovirus - immunology; Cytomegalovirus Infections - etiology; Cytomegalovirus Infections - immunology; Female; Hematopoietic Stem Cell Transplantation - adverse effects; Humans; Immunologic Memory; Killer Cells, Natural - immunology; Male; Middle Aged; Quinazolines - pharmacology; Quinazolines - therapeutic use; T-Lymphocytes - immunology; Transplantation; Virus Activation
• ISSN: 2473-9529; 2473-9537; 2473-9537
• DOI: 10.1182/bloodadvances.2023012008

•Clinically significant HCMV reactivation after letermovir cessation is associated with both T-cell and “memory-like” NK-cell impairments.•HCMV manifestation severity is linked to the magnitude of impaired HCMV–specific T and “memory-like” NK-cell reconstitution post-letermovir. [Display omitted] Allogeneic hematopoietic stem cell transplantation (alloSCT) is the only cure for many hematologic malignancies. However, alloSCT recipients are susceptible to opportunistic pathogens, such as human cytomegalovirus (HCMV). Letermovir prophylaxis has revolutionized HCMV management, but the challenge of late HCMV reactivations has emerged. Immunological surrogates of clinically significant HCMV infection (csCMVi) after discontinuation of letermovir remain to be defined. Therefore, we studied natural killer (NK)-cell reconstitution along with the global and HCMV pp65-specific T-cell repertoire of 24 alloSCT recipients at 7 time points before (day +90) and after (days +120-270) cessation of letermovir prophylaxis. Patients who experienced csCMVi had lower counts of IFN-γ+ HCMV–specific CD4+ and CD8+ T cells than HCMV controllers. Furthermore, patients with csCMVi displayed late impairment of NK-cell reconstitution, especially suppression of “memory-like” CD159c+CD56dim NK-cell counts that preceded csCMVi events in most patients. Moreover, several surrogates of immune reconstitution were associated with the severity of HCMV manifestation, with patients suffering from HCMV end-organ disease and/or refractory HCMV infection harboring least HCMV–specific T cells and “memory-like” NK cells. Altogether, our findings establish an association of delayed or insufficient proliferation of both HCMV–specific T cells and “memory-like” NK cells with csCMVi and the severity of HCMV manifestations after discontinuation of letermovir prophylaxis.