Nirmatrelvir treatment of SARS-CoV-2-infected mice blunts antiviral adaptive immune responses

被引：15

作者：

Fumagalli, Valeria ^{[1
,2
]}

Di Lucia, Pietro ^{[1
,2
]}

Rava, Micol ^{[1
,2
]}

Marotta, Davide ^{[1
,2
]}

Bono, Elisa ^{[1
]}

Grassi, Stefano ^{[3
]}

Donnici, Lorena ^{[4
]}

Cannalire, Rolando ^{[5
]}

Stefanelli, Irina ^{[5
]}

Ferraro, Anastasia ^{[5
]}

Esposito, Francesca ^{[6
]}

Pariani, Elena ^{[7
]}

Inverso, Donato ^{[1
,2
]}

Montesano, Camilla ^{[8
]}

Delbue, Serena ^{[9
]}

Perlman, Stanley ^{[10
,11
]}

Tramontano, Enzo ^{[6
]}

De Francesco, Raffaele ^{[4
,12
]}

Summa, Vincenzo ^{[5
]}

Guidotti, Luca G. ^{[1
,2
]}

Iannacone, Matteo ^{[1
,2
,13
]}

机构：

[1] IRCCS San Raffaele Sci Inst, Div Immunol Transplantat & Infect Dis, Milan, Italy

[2] Univ Vita Salute San Raffaele, Milan, Italy

[3] IRCCS San Raffaele Sci Inst, Pathol Unit, Milan, Italy

[4] INGM Ist Nazl Genet Mol Romeo & Erica Invernizzi, Milan, Italy

[5] Univ Naples Federico II, Sch Med & Surg, Dept Pharm, Naples, Italy

[6] Cittadella Univ Monserrato, Dipartimento Sci Vita & Ambiente, Cagliari, Italy

[7] Univ Milan, Dept Biomed Sci Hlth, Milan, Italy

[8] Univ Roma La Sapienza, Dept Chem, Rome, Italy

[9] Univ Milan, Dept Biomed Surg & Dent Sci, Milan, Italy

[10] Univ Iowa, Dept Microbiol & Immunol, Iowa City, IA USA

[11] Univ Iowa, Dept Pediat, Iowa City, IA 52242 USA

[12] Univ Milan, Dept Pharmacol & Biomol Sci, Milan, Italy

[13] IRCCS San Raffaele Sci Inst, Expt Imaging Ctr, Milan, Italy

来源：

EMBO MOLECULAR MEDICINE | 2023年 / 15卷 / 05期

基金：

欧洲研究理事会;

关键词：

adaptive immunity; animal models; antiviral treatment; nirmatrelvir; SARS-CoV-2;

D O I：

10.15252/emmm.202317580

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

Alongside vaccines, antiviral drugs are becoming an integral part of our response to the SARS-CoV-2 pandemic. Nirmatrelvir-an orally available inhibitor of the 3-chymotrypsin-like cysteine protease-has been shown to reduce the risk of progression to severe COVID-19. However, the impact of nirmatrelvir treatment on the development of SARS-CoV-2-specific adaptive immune responses is unknown. Here, by using mouse models of SARS-CoV-2 infection, we show that nirmatrelvir administration blunts the development of SARS-CoV-2-specific antibody and T cell responses. Accordingly, upon secondary challenge, nirmatrelvir-treated mice recruited significantly fewer memory T and B cells to the infected lungs and mediastinal lymph nodes, respectively. Together, the data highlight a potential negative impact of nirmatrelvir treatment with important implications for clinical management and might help explain the virological and/or symptomatic relapse after treatment completion reported in some individuals.

引用

页数：13

共 37 条

[1] CD8+ T cell contraction is controlled by early inflammation [J].

Badovinac, VP ;

Porter, BB ;

Harty, JT .

NATURE IMMUNOLOGY, 2004, 5 (08) :809-817

[2] Dynamics and genomic landscape of CD8+ T cells undergoing hepatic priming [J].

Benechet, Alexandre P. ;

De Simone, Giorgia ;

Di Lucia, Pietro ;

Cilenti, Francesco ;

Barbiera, Giulia ;

Le Bert, Nina ;

Fumagalli, Valeria ;

Lusito, Eleonora ;

Moalli, Federica ;

Bianchessi, Valentina ;

Andreata, Francesco ;

Zordan, Paola ;

Bono, Elisa ;

Giustini, Leonardo ;

Bonilla, Weldy V. ;

Bleriot, Camille ;

Kunasegaran, Kamini ;

Gonzalez-Aseguinolaza, Gloria ;

Pinschewer, Daniel D. ;

Kennedy, Patrick T. F. ;

Naldini, Luigi ;

Kuka, Mirela ;

Ginhoux, Florent ;

Cantore, Alessio ;

Bertoletti, Antonio ;

Ostuni, Renato ;

Guidotti, Luca G. ;

Iannacone, Matteo .

NATURE, 2019, 574 (7777) :200-+

[3] Characterization of Virologic Rebound Following Nirmatrelvir-Ritonavir Treatment for Coronavirus Disease 2019 (COVID-19) [J].

Boucau, Julie ;

Uddin, Rockib ;

Marino, Caitlin ;

Regan, James ;

Flynn, James P. ;

Choudhary, Manish C. ;

Chen, Geoffrey ;

Stuckwisch, Ashley M. ;

Mathews, Josh ;

Liew, May Y. ;

Singh, Arshdeep ;

Reynolds, Zahra ;

Iyer, Surabhi L. ;

Chamberlin, Grace C. ;

Vyas, Tammy D. ;

Vyas, Jatin M. ;

Turbett, Sarah E. ;

Li, Jonathan Z. ;

Lemieux, Jacob E. ;

Barczak, Amy K. ;

Siedner, Mark J. .

CLINICAL INFECTIOUS DISEASES, 2023, 76 (03) :E526-E529

[4] Targeting SARS-CoV-2 Proteases and Polymerase for COVID-19 Treatment: State of the Art and Future Opportunities [J].

Cannalire, Rolando ;

Cerchia, Carmen ;

Beccari, Andrea R. ;

Di Leva, Francesco Saverio ;

Summa, Vincenzo .

JOURNAL OF MEDICINAL CHEMISTRY, 2022, 65 (04) :2716-2746

[5]

Charness M., 2022, RAPID RELAPSE SYMPTO, DOI [10.21203/rs.3.rs-1588371/v2, DOI 10.21203/RS.3.RS-1588371/V2]

[6] Rebound of SARS-CoV-2 Infection after Nirmatrelvir-Ritonavir Treatment [J].

Charness, Michael E. ;

Gupta, Kalpana ;

Stack, Gary ;

Strymish, Judith ;

Adams, Eleanor ;

Lindy, David C. ;

Mohri, Hiroshi ;

Ho, David D. .

NEW ENGLAND JOURNAL OF MEDICINE, 2022, 387 (11) :1045-1047

[7] COVID-eVax, an electroporated DNA vaccine candidate encoding the SARS-CoV-2 RBD, elicits protective responses in animal models [J].

Conforti, Antonella ;

Marra, Emanuele ;

Palombo, Fabio ;

Roscilli, Giuseppe ;

Rava, Micol ;

Fumagalli, Valeria ;

Muzi, Alessia ;

Maffei, Mariano ;

Luberto, Laura ;

Lione, Lucia ;

Salvatori, Erika ;

Compagnone, Mirco ;

Pinto, Eleonora ;

Pavoni, Emiliano ;

Bucci, Federica ;

Vitagliano, Grazia ;

Stoppoloni, Daniela ;

Pacello, Maria Lucrezia ;

Cappelletti, Manuela ;

Ferrara, Fabiana Fosca ;

D'Acunto, Emanuela ;

Chiarini, Valerio ;

Arriga, Roberto ;

Nyska, Abraham ;

Di Lucia, Pietro ;

Marotta, Davide ;

Bono, Elisa ;

Giustini, Leonardo ;

Sala, Eleonora ;

Perucchini, Chiara ;

Paterson, Jemma ;

Ryan, Kathryn Ann ;

Challis, Amy-Rose ;

Matusali, Giulia ;

Colavita, Francesca ;

Caselli, Gianfranco ;

Criscuolo, Elena ;

Clementi, Nicola ;

Mancini, Nicasio ;

Gross, Ruediger ;

Seidel, Alina ;

Wettstein, Lukas ;

Muench, Jan ;

Donnici, Lorena ;

Conti, Matteo ;

De Francesco, Raffaele ;

Kuka, Mirela ;

Ciliberto, Gennaro ;

Castilletti, Concetta ;

Capobianchi, Maria Rosaria .

MOLECULAR THERAPY, 2022, 30 (01) :311-326

[8] Duration of infection and antigen display have minimal influence on the kinetics of the CD4+ T cell response to Listeria monocytogenes infection [J].

Corbin, GA ;

Harty, JT .

JOURNAL OF IMMUNOLOGY, 2004, 173 (09) :5679-5687

[9] Structural and Biochemical Analysis of the Dual Inhibition of MG-132 against SARS-CoV-2 Main Protease (Mpro/3CLpro) and Human Cathepsin-L [J].

Costanzi, Elisa ;

Kuzikov, Maria ;

Esposito, Francesca ;

Albani, Simone ;

Demitri, Nicola ;

Giabbai, Barbara ;

Camasta, Marianna ;

Tramontano, Enzo ;

Rossetti, Giulia ;

Zaliani, Andrea ;

Storici, Paola .

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 2021, 22 (21)

[10]

Dai EY, 2022, medRxiv, DOI [10.1101/2022.08.04.22278378, 10.1101/2022.08.04.22278378, DOI 10.1101/2022.08.04.22278378]

← 1 2 3 4 →