Author: Raikelkar, Jayant ; Yuzefpolskaya, Melana ; Pereira, Marcus R. ; Mabasa, Angelo ; Colombo, Paolo C. ; Majure, David ; Choe, Jason ; DeFilippis, Ersilia M. ; Sayer, Gabriel ; Batra, Jaya ; Hi Lee, Sun ; Fried, Justin ; Carey, Matt ; Restaino, Susan ; Clerkin, Kevin ; Uriel, Nir ; Jennings, Douglas ; Uriel, Matan ; Latif, Farhana ; Golob, Stephanie ; Gaine, Maureen

AbstractLetermovir is a novel agent for the prevention of cytomegalovirus (CMV) infection and disease that, unlike traditional CMV DNA polymerase inhibitors, does not carry the risk of myelosuppression. The purpose of this study was to evaluate the safety, efficacy, and clinical application of letermovir for CMV prophylaxis in heart transplant (HT) recipients. Between November 1, 2019, and October 1, 2021, at a single, tertiary care hospital, 17 HT recipients were initiated on letermovir due to leukopenia while on valganciclovir. Fifteen (88%) had high‐risk mismatch (CMV D+/R‐). Median time on letermovir was 5 months (interquartile range, 2–8 months.) At the end of the study period, nine of 17 patients (52.9%) were still on letermovir and four of the 17 (23.5%) had successfully completed the prophylaxis window on letermovir and been switched to the pre‐emptive strategy. One patient developed clinically significant CMV viremia in the setting of being unable to obtain medication due to insurance barriers but was later successfully restarted on letermovir. One patient was unable to tolerate letermovir due to symptoms of headache and myalgias. Two patients developed low‐level non‐clinically significant CMV viremia and were switched back to valacyclovir. All patients had tacrolimus dosages reduced at time of letermovir initiation to minimize the risk of supratherapeutic tacrolimus concentration. One patient required hospitalization due to symptomatic tacrolimus toxicity. For HT recipients who cannot tolerate valganciclovir, letermovir presents an alternative for CMV prophylaxis. Close monitoring for breakthrough CMV and calcineurin inhibitor levels is necessary. Larger studies are required to further delineate its use and help provide further evidence of its safety and efficacy.

PLOS Pathogens

Cytomegalovirus inhibitors of programmed cell death restrict antigen cross-presentation in the priming of antiviral CD8 T cells

Article

Author: Brinkmann, Melanie M ; Reddehase, Matthias J ; Holtappels, Rafaela ; Brune, Wolfram ; Büttner, Julia K ; Böhm, Verena ; Lemmermann, Niels A W ; Ebert, Stefan

CD8 T cells are the predominant effector cells of adaptive immunity in preventing cytomegalovirus (CMV) multiple-organ disease caused by cytopathogenic tissue infection. The mechanism by which CMV-specific, naïve CD8 T cells become primed and clonally expand is of fundamental importance for our understanding of CMV immune control. For CD8 T-cell priming, two pathways have been identified: direct antigen presentation by infected professional antigen-presenting cells (pAPCs) and antigen cross-presentation by uninfected pAPCs that take up antigenic material derived from infected tissue cells. Studies in mouse models using murine CMV (mCMV) and precluding either pathway genetically or experimentally have shown that, in principle, both pathways can congruently generate the mouse MHC/H-2 class-I-determined epitope-specificity repertoire of the CD8 T-cell response. Recent studies, however, have shown that direct antigen presentation is the canonical pathway when both are accessible. This raised the question of why antigen cross-presentation is ineffective even under conditions of high virus replication thought to provide high amounts of antigenic material for feeding cross-presenting pAPCs. As delivery of antigenic material for cross-presentation is associated with programmed cell death, and as CMVs encode inhibitors of different cell death pathways, we pursued the idea that these inhibitors restrict antigen delivery and thus CD8 T-cell priming by cross-presentation. To test this hypothesis, we compared the CD8 T-cell responses to recombinant mCMVs lacking expression of the apoptosis-inhibiting protein M36 or the necroptosis-inhibiting protein M45 with responses to wild-type mCMV and revertant viruses expressing the respective cell death inhibitors. The data reveal that increased programmed cell death improves CD8 T-cell priming in mice capable of antigen cross-presentation but not in a mutant mouse strain unable to cross-present. These findings strongly support the conclusion that CMV cell death inhibitors restrict the priming of CD8 T cells by antigen cross-presentation.

100 Deals associated with CMV protein inhibitors(Merck)

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Indication	Highest Phase	Country/Location	Organization	Date
Cytomegalovirus Infections	Preclinical	US	Merck & Co., Inc.	09 Jul 2024
Herpes Simplex	Preclinical	US	Merck & Co., Inc.	09 Jul 2024

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