Orally efficacious broad-spectrum ribonucleoside analog inhibitor of influenza and respiratory syncytial viruses

Antimicrobial Agents and Chemotherapy

Volumn 62, Issue 8, 2018, Pages

  Yoon, Jeong Joong ^a   Toots, Mart ^a   Lee, Sujin ^b,c   Lee, Myung Eun ^a   Ludeke, Barbara ^d   Luczo, Jasmina M ^e   Ganti, Ketaki ^b   Cox, Robert M ^a   Sticher, Zachary M ^f   Edpuganti, Vindya ^f   Mitchell, Deborah G ^f   Lockwood, Mark A ^f   Kolykhalov, Alexander A ^f   Greninger, Alexander L ^g   Moore, Martin L ^b,c   Painter, George R ^f   Lowen, Anice C ^b   Tompkins, Stephen M ^e   Fearns, Rachel ^d   Natchus, Michael G ^f   Plemper, Richard K ^a   more..

^a GEORGIA STATE UNIVERSITY   (United States)

^b EMORY UNIVERSITY SCHOOL OF MEDICINE   (United States)

^c CHILDREN'S HEALTHCARE OF ATLANTA   (United States)

^d BOSTON UNIVERSITY SCHOOL OF MEDICINE   (United States)

^e UNIVERSITY OF GEORGIA   (United States)

^f EMORY UNIVERSITY   (United States)

^g UNIVERSITY OF WASHINGTON   (United States)

Author keywords

Antiviral agents; Influenza; Nucleoside analogs; Respiratory syncytial virus

Indexed keywords

ANTIVIRUS AGENT; CL 309623; CYTIDINE; FAVIPIRAVIR; GRP 71271; LUMICITABINE; N4 HYDROXYCYTIDINE; OSELTAMIVIR; RIBONUCLEOSIDE DERIVATIVE; RNA DIRECTED RNA POLYMERASE; UNCLASSIFIED DRUG; VIRUS RNA;

AIRWAY CELL; ANIMAL CELL; ANIMAL TISSUE; ARTICLE; AVIAN INFLUENZA VIRUS; BRONCHUS EPITHELIUM; CELL CULTURE; CONTROLLED STUDY; DRUG BIOAVAILABILITY; DRUG HALF LIFE; EPITHELIUM CELL; FEMALE; GUINEA PIG; HIGH THROUGHPUT SCREENING; HUMAN; HUMAN CELL; HUMAN RESPIRATORY SYNCYTIAL VIRUS; IN VITRO STUDY; INFLUENZA A VIRUS; INFLUENZA B VIRUS; INFLUENZA VIRUS; LUNG PARENCHYMA; MOUSE; MUTAGENESIS; NONHUMAN; PARAMETERS; PNEUMOVIRUS; PRIORITY JOURNAL; RNA SEQUENCE; SWINE INFLUENZA VIRUS; TIME TO MAXIMUM PLASMA CONCENTRATION; TRACHEA EPITHELIUM; VIRUS LOAD; VOLUME OF DISTRIBUTION; ANIMAL; DRUG EFFECT; GENETICS;

ANIMALS; ANTIVIRAL AGENTS; CELLS, CULTURED; GUINEA PIGS; HUMANS; INFLUENZA A VIRUS; INFLUENZA B VIRUS; MICE; RESPIRATORY SYNCYTIAL VIRUS, HUMAN; RESPIRATORY SYNCYTIAL VIRUSES; RNA, VIRAL;

EID: 85052024066     PISSN: 00664804     EISSN: 10986596     Source Type: Journal    
DOI: 10.1128/AAC.00766-18     Document Type: Article

References (83)

1. Zhou H, Thompson WW, Viboud CG, Ringholz CM, Cheng PY, Steiner C, Abedi GR, Anderson LJ, Brammer L, Shay DK. 2012. Hospitalizations associated with influenza and respiratory syncytial virus in the United States, 1993-2008. Clin Infect Dis 54:1427–1436. https://doi.org/10.1093/cid/cis211.
2. Falsey AR, Hennessey PA, Formica MA, Cox C, Walsh EE. 2005. Respiratory syncytial virus infection in elderly and high-risk adults. N Engl J Med 352:1749 –1759. https://doi.org/10.1056/NEJMoa043951.
3. Thompson WW, Shay DK, Weintraub E, Brammer L, Cox N, Anderson LJ, Fukuda K. 2003. Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA 289:179–186. https://doi.org/10.1001/jama.289.2.179.
4. Stiver G. 2003. The treatment of influenza with antiviral drugs. CMAJ 168:49–56.
5. Skowronski DM, Chambers C, De Serres G, Dickinson JA, Winter A-L, Hickman R, Chan T, Jassem AN, Drews SJ, Charest H, Gubbay JB, Bastien N, Li Y, Krajden M. 2018. Early season co-circulation of influenza A(H3N2) and B(Yamagata): interim estimates of 2017/18 vaccine effectiveness, Canada, January 2018. Euro Surveill 23:pii18-00035. https://doi.org/10.2807/1560-7917.ES.2018.23.5.18-00035.
6. Broor S, Parveen S, Bharaj P, Prasad VS, Srinivasulu KN, Sumanth KM, Kapoor SK, Fowler K, Sullender WM. 2007. A prospective three-year cohort study of the epidemiology and virology of acute respiratory infections of children in rural India. PLoS One 2:e491. https://doi.org/10.1371/journal.pone.0000491.
7. Mahadevia PJ, Makari D, Masaquel A. 2012. Methodological concerns regarding cost-effectiveness analysis of palivizumab in Florida Medicaid. Arch Pediatr Adolesc Med 166:968 –970. https://doi.org/10.1001/archpediatrics.2012.1591.
8. Mahadevia PJ, Masaquel AS, Polak MJ, Weiner LB. 2012. Cost utility of palivizumab prophylaxis among pre-term infants in the United States: a national policy perspective. J Med Econ 15:987–996. https://doi.org/10.3111/13696998.2012.690013.
9. Weiner LB, Masaquel AS, Polak MJ, Mahadevia PJ. 2012. Cost-effectiveness analysis of palivizumab among pre-term infant populations covered by Medicaid in the United States. J Med Econ 15:997–1018. https://doi.org/10.3111/13696998.2012.672942.
10. Kamal-Bahl S, Doshi J, Campbell J. 2002. Economic analyses of respiratory syncytial virus immunoprophylaxis in high-risk infants: a systematic review. Arch Pediatr Adolesc Med 156:1034–1041. https://doi.org/10.1001/archpedi.156.10.1034.
11. Hampp C, Kauf TL, Saidi AS, Winterstein AG. 2011. Cost-effectiveness of respiratory syncytial virus prophylaxis in various indications. Arch Pediatr Adolesc Med 165:498 –505. https://doi.org/10.1001/archpediatrics.2010.298.
12. De Vincenzo JP, El Saleeby CM, Bush AJ. 2005. Respiratory syncytial virus load predicts disease severity in previously healthy infants. J Infect Dis 191:1861–1868. https://doi.org/10.1086/430008.
13. El Saleeby CM, Bush AJ, Harrison LM, Aitken JA, Devincenzo JP. 2011. Respiratory syncytial virus load, viral dynamics, and disease severity in previously healthy naturally infected children. J Infect Dis 204:996 –1002. https://doi.org/10.1093/infdis/jir494.
14. Fiore AE, Fry A, Shay D, Gubareva L, Bresee JS, Uyeki TM, Centers for Disease Control and Prevention. 2011. Antiviral agents for the treatment and chemoprophylaxis of influenza—recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recommend Rep 60:1–24.
15. Salerno D, Hasham MG, Marshall R, Garriga J, Tsygankov AY, Grana X. 2007. Direct inhibition of CDK9 blocks HIV-1 replication without preventing T-cell activation in primary human peripheral blood lymphocytes. Gene 405:65–78. https://doi.org/10.1016/j.gene.2007.09.010.
16. Schang LM. 2006. First demonstration of the effectiveness of inhibitors of cellular protein kinases in antiviral therapy. Expert Rev Anti Infect Ther 4:953–956. https://doi.org/10.1586/14787210.4.6.953.
17. Prussia A, Thepchatri P, Snyder JP, Plemper RK. 2011. Systematic approaches towards the development of host-directed antiviral therapeutics. Int J Mol Sci 12:4027–4052. https://doi.org/10.3390/ijms12064027.
18. Kaufmann SHE, Dorhoi A, Hotchkiss RS, Bartenschlager R. 22 September 2017. Host-directed therapies for bacterial and viral infections. Nat Rev Drug Discov https://doi.org/10.1038/nrd.2017.162.
19. Shaw ML. 2017. The next wave of influenza drugs. ACS Infect Dis 3:691–694. https://doi.org/10.1021/acsinfecdis.7b00142.
20. Dahlin JL, Walters MA. 2014. The essential roles of chemistry in high-throughput screening triage. Future Med Chem 6:1265–1290. https://doi.org/10.4155/fmc.14.60.
21. Baell J, Walters MA. 2014. Chemistry: chemical con artists foil drug discovery. Nature 513:481–483. https://doi.org/10.1038/513481a.
22. Baell JB, Holloway GA. 2010. New substructure filters for removal of pan assay interference compounds (PAINS) from screening libraries and for their exclusion in bioassays. J Med Chem 53:2719–2740. https://doi.org/10.1021/jm901137j.
23. Webster RG, Govorkova EA. 2014. Continuing challenges in influenza. Ann N Y Acad Sci 1323:115–139. https://doi.org/10.1111/nyas.12462.
24. Voss ME, Carter PH, Tebben AJ, Scherle PA, Brown GD, Thompson LA, Xu M, Lo YC, Yang G, Liu RQ, Strzemienski P, Everlof JG, Trzaskos JM, Decicco CP. 2003. Both 5-arylidene-2-thioxodihydropyrimidine-4,6(1H,5H)-diones and 3-thioxo-2,3-dihydro-1H-imidazo[1,5-a]indol-1-ones are light-dependent tumor necrosis factor-alpha antagonists. Bioorg Med Chem Lett 13:533–538. https://doi.org/10.1016/S0960-894X(02)00941-1.
25. Anderson LJ, Parker RA, Strikas RL. 1990. Association between respiratory syncytial virus outbreaks and lower respiratory tract deaths of infants and young children. J Infect Dis 161:640–646. https://doi.org/10.1093/infdis/161.4.640.
26. Groothuis JR, Woodin KA, Katz R, Robertson AD, McBride JT, Hall CB, McWilliams BC, Lauer BA. 1990. Early ribavirin treatment of respiratory syncytial viral infection in high-risk children. J Pediatr 117:792–798. https://doi.org/10.1016/S0022-3476(05)83347-5.
27. Anonymous. 2014. Summary of media conference by Tamura Ministry of Health, Welfare and Labor, on August 15, 2014. Ministry of Health, Welfare and Labor, Tokyo, Japan. (In Japanese.) http://www.mhlw.go.jp/stf/kaiken/daijin/0000054819.html.
28. DeVincenzo J, Fathi H, McClure M, Westland C, Chanda S, Lambkin-Williams R, Smith P, Harrison L, Symons J, Scaglioni-Weinlich C, Zhang Q, Nieforth K, Beigelman L, Blatt L, Fry J. 2014. Treatment with oral ALS-008176, a nucleoside analog, rapidly reduces RSV viral load and clinical disease severity in a healthy volunteer challenge study. Open Forum Infect Dis 1:S66. https://doi.org/10.1093/ofid/ofu083.01.
29. Deval J, Hong J, Wang G, Taylor J, Smith LK, Fung A, Stevens SK, Liu H, Jin Z, Dyatkina N, Prhavc M, Stoycheva AD, Serebryany V, Liu J, Smith DB, Tam Y, Zhang Q, Moore ML, Fearns R, Chanda SM, Blatt LM, Symons JA, Beigelman L. 2015. Molecular basis for the selective inhibition of respiratory syncytial virus RNA polymerase by 2=-fluoro-4=-chloromethyl-cytidine triphosphate. PLoS Pathog 11:e1004995. https://doi.org/10.1371/journal.ppat.1004995.
30. Yan D, Weisshaar M, Lamb K, Chung HK, Lin MZ, Plemper RK. 2015. Replication-competent influenza virus and respiratory syncytial virus luciferase reporter strains engineered for co-infections identify antiviral compounds in combination screens. Biochemistry 54: 5589–5604. https://doi.org/10.1021/acs.biochem.5b00623.
31. Jimenez-Somarribas A, Mao S, Yoon JJ, Weisshaar M, Cox RM, Marengo JR, Mitchell DG, Morehouse ZP, Yan D, Solis I, Liotta DC, Natchus MG, Plemper RK. 2017. Identification of non-nucleoside inhibitors of the respiratory syncytial virus polymerase complex. J Med Chem 60: 2305–2325. https://doi.org/10.1021/acs.jmedchem.6b01568.
32. Weisshaar M, Cox R, Morehouse Z, Kumar Kyasa S, Yan D, Oberacker P, Mao S, Golden JE, Lowen AC, Natchus MG, Plemper RK. 2016. Identification and characterization of influenza virus entry inhibitors through dual myxovirus high-throughput screening. J Virol 90:7368–7387. https://doi.org/10.1128/JVI.00898-16.
33. Hoffmann HH, Kunz A, Simon VA, Palese P, Shaw ML. 2011. Broad-spectrum antiviral that interferes with de novo pyrimidine biosynthesis. Proc Natl Acad Sci U S A 108:5777–5782. https://doi.org/10.1073/pnas.1101143108.
34. Krumm SA, Ndungu JM, Yoon JJ, Dochow M, Sun A, Natchus M, Snyder JP, Plemper RK. 2011. Potent host-directed small-molecule inhibitors of myxovirus RNA-dependent RNA-polymerases. PLoS One 6:e20069. https://doi.org/10.1371/journal.pone.0020069.
35. Glezen WP, Schmier JK, Kuehn CM, Ryan KJ, Oxford J. 2013. The burden of influenza B: a structured literature review. Am J Public Health 103: e43–e51. https://doi.org/10.2105/AJPH.2012.301137.
36. 4-Hydroxycytidine is a potent anti-alphavirus compound that induces high level of mutations in viral genome. J Virol https://doi.org/10.1128/JVI.01965-17.
37. 4-hydroxycytidine as a novel inhibitor of chikungunya virus. Antimicrob Agents Chemother 61:e02395-16. https://doi.org/10.1128/AAC.02395-16.
38. Hollecker L, Choo H, Chong Y, Chu CK, Lostia S, McBrayer TR, Stuyver LJ, Mason JC, Du J, Rachakonda S, Shi J, Schinazi RF, Watanabe KA. 2004. Synthesis of beta-enantiomers of N4-hydroxy-3=-deoxypyrimidine nucleosides and their evaluation against bovine viral diarrhoea virus and hepatitis C virus in cell culture. Antivir Chem Chemother 15:43–55. https://doi.org/10.1177/095632020401500105.
39. Barnard DL, Hubbard VD, Burton J, Smee DF, Morrey JD, Otto MJ, Sidwell RW. 2004. Inhibition of severe acute respiratory syndrome-associated coronavirus (SARSCoV) by calpain inhibitors and beta-D-N4-hydroxycytidine. Antivir Chem Chemother 15:15–22. https://doi.org/10.1177/095632020401500102.
40. Noton SL, Deflube LR, Tremaglio CZ, Fearns R. 2012. The respiratory syncytial virus polymerase has multiple RNA synthesis activities at the promoter. PLoS Pathog 8:e1002980. https://doi.org/10.1371/journal.ppat.1002980.
41. Les A, Adamowicz L, Rode W. 1993. Structure and conformation of N4-hydroxycytosine and N4-hydroxy-5-fluorocytosine. A theoretical ab initio study. Biochim Biophys Acta 1173:39–48. https://doi.org/10.1016/0167-4781(93)90240-E.
42. Crotty S, Cameron CE, Andino R. 2001. RNA virus error catastrophe: direct molecular test by using ribavirin. Proc Natl Acad Sci U S A 98:6895–6900. https://doi.org/10.1073/pnas.111085598.
43. Stuyver LJ, Whitaker T, McBrayer TR, Hernandez-Santiago BI, Lostia S, Tharnish PM, Ramesh M, Chu CK, Jordan R, Shi J, Rachakonda S, Watanabe KA, Otto MJ, Schinazi RF. 2003. Ribonucleoside analogue that blocks replication of bovine viral diarrhea and hepatitis C viruses in culture. Antimicrob Agents Chemother 47:244–254. https://doi.org/10.1128/AAC.47.1.244-254.2003.
44. Moore ML, Chi MH, Luongo C, Lukacs NW, Polosukhin VV, Huckabee MM, Newcomb DC, Buchholz UJ, Crowe JE, Jr, Goleniewska K, Williams JV, Collins PL, Peebles RS, Jr. 2009. A chimeric A2 strain of respiratory syncytial virus (RSV) with the fusion protein of RSV strain line 19 exhibits enhanced viral load, mucus, and airway dysfunction. J Virol 83: 4185–4194. https://doi.org/10.1128/JVI.01853-08.
45. Chockalingam AK, Hamed S, Goodwin DG, Rosenzweig BA, Pang E, Boyne MT, II, Patel V. 2016. The effect of oseltamivir on the disease progression of lethal influenza A virus infection: plasma cytokine and miRNA responses in a mouse model. Dis Markers 2016:9296457. https://doi.org/10.1155/2016/9296457.
46. Yen HL, Aldridge JR, Boon AC, Ilyushina NA, Salomon R, Hulse-Post DJ, Marjuki H, Franks J, Boltz DA, Bush D, Lipatov AS, Webby RJ, Rehg JE, Webster RG. 2009. Changes in H5N1 influenza virus hemagglutinin receptor binding domain affect systemic spread. Proc Natl Acad Sci U S A 106: 286–291. https://doi.org/10.1073/pnas.0811052106.
47. Bouvier NM, Lowen AC. 2010. Animal models for influenza virus pathogenesis and transmission. Viruses 2:1530–1563. https://doi.org/10.3390/v20801530.
48. Lowen AC, Mubareka S, Tumpey TM, Garcia-Sastre A, Palese P. 2006. The guinea pig as a transmission model for human influenza viruses. Proc Natl Acad Sci U S A 103:9988–9992. https://doi.org/10.1073/pnas.0604157103.
49. Baranovich T, Wong SS, Armstrong J, Marjuki H, Webby RJ, Webster RG, Govorkova EA. 2013. T-705 (favipiravir) induces lethal mutagenesis in influenza A H1N1 viruses in vitro. J Virol 87:3741–3751. https://doi.org/10.1128/JVI.02346-12.
50. Crotty S, Maag D, Arnold JJ, Zhong W, Lau JY, Hong Z, Andino R, Cameron CE. 2000. The broad-spectrum antiviral ribonucleoside ribavirin is an RNA virus mutagen. Nat Med 6:1375–1379. https://doi.org/10.1038/82191.
51. Banks GR, Brown DM, Streeter DG, Grossman L. 1971. Mutagenic analogues of cytosine: RNA polymerase template and substrate studies. J Mol Biol 60:425–439. https://doi.org/10.1016/0022-2836(71)90179-3.
52. Budowsky EI, Sverdlov ED, Monastyrskaya GS. 1972. New method of selective and rapid modification of the cytidine residues. FEBS Lett 25:201–204. https://doi.org/10.1016/0014-5793(72)80485-X.
53. Traut TW. 1994. Physiological concentrations of purines and pyrimidines. Mol Cell Biochem 140:1–22. https://doi.org/10.1007/BF00928361.
54. Lauring AS, Frydman J, Andino R. 2013. The role of mutational robustness in RNA virus evolution. Nat Rev Microbiol 11:327–336. https://doi.org/10.1038/nrmicro3003.
55. Crotty S, Andino R. 2002. Implications of high RNA virus mutation rates: lethal mutagenesis and the antiviral drug ribavirin. Microbes Infect 4:1301–1307. https://doi.org/10.1016/S1286-4579(02)00008-4.
56. Pauly MD, Lauring AS. 2015. Effective lethal mutagenesis of influenza virus by three nucleoside analogs. J Virol 89:3584–3597. https://doi.org/10.1128/JVI.03483-14.
57. Jin Z, Smith LK, Rajwanshi VK, Kim B, Deval J. 2013. The ambiguous base-pairing and high substrate efficiency of T-705 (favipiravir) ribofura-nosyl 5=-triphosphate towards influenza A virus polymerase. PLoS One 8:e68347. https://doi.org/10.1371/journal.pone.0068347.
58. Graci JD, Cameron CE. 2006. Mechanisms of action of ribavirin against distinct viruses. Rev Med Virol 16:37–48. https://doi.org/10.1002/rmv.483.
59. Salganik RI, Vasjunina EA, Poslovina AS, Andreeva IS. 1973. Mutagenic action of N4-hydroxycytidine on Escherichia coli B cyt. Mutat Res 20:1–5. https://doi.org/10.1016/0027-5107(73)90091-2.
60. Jakobs HH, Froriep D, Havemeyer A, Mendel RR, Bittner F, Clement B. 2014. The mitochondrial amidoxime reducing component (mARC): involvement in metabolic reduction of N-oxides, oximes and N-hydroxyamidinohydrazones. ChemMedChem 9:2381–2387. https://doi.org/10.1002/cmdc.201402127.
61. Janion C. 1984. Some problems of mutagenesis induced by base analogues. Acta Biochim Pol 31:183–192.
62. Yan D, Lee S, Thakkar VD, Luo M, Moore ML, Plemper RK. 2014. Cross-resistance mechanism of respiratory syncytial virus against structurally diverse entry inhibitors. Proc Natl Acad Sci U S A 111:E3441–E3449. https://doi.org/10.1073/pnas.1405198111.
63. Krumm SA, Yan D, Hovingh ES, Evers TJ, Enkirch T, Reddy GP, Sun A, Saindane MT, Arrendale RF, Painter G, Liotta DC, Natchus MG, von Messling V, Plemper RK. 2014. An orally available, small-molecule polymerase inhibitor shows efficacy against a lethal morbillivirus infection in a large animal model. Sci Transl Med 6:232ra52. https://doi.org/10.1126/scitranslmed.3008517.
64. CDC. 2006. High levels of adamantane resistance among influenza A (H3N2) viruses and interim guidelines for use of antiviral agents—United States, 2005-06 influenza season. JAMA 295:881– 882. https://doi.org/10.1001/jama.295.8.881.
65. Okomo-Adhiambo M, Nguyen HT, Abd Elal A, Sleeman K, Fry AM, Gubareva LV. 2014. Drug susceptibility surveillance of influenza viruses circulating in the United States in 2011-2012: application of the WHO antiviral working group criteria. Influenza Other Respir Viruses 8:258–265. https://doi.org/10.1111/irv.12215.
66. Marjuki H, Mishin VP, Chesnokov AP, Jones J, De La Cruz JA, Sleeman K, Tamura D, Nguyen HT, Wu HS, Chang FY, Liu MT, Fry AM, Cox NJ, Villanueva JM, Davis CT, Gubareva LV. 14 August 2014. Characterization of drug-resistant influenza A(H7N9) variants isolated from an oseltamivir-treated patient in Taiwan. J Infect Dis https://doi.org/10.1093/infdis/jiu447.
67. Nguyen HT, Fry AM, Gubareva LV. 2012. Neuraminidase inhibitor resistance in influenza viruses and laboratory testing methods. Antivir Ther 17:159–173. https://doi.org/10.3851/IMP2067.
68. McKimm-Breschkin JL, Williams J, Barrett S, Jachno K, McDonald M, Mohr PG, Saito T, Tashiro M. 2013. Reduced susceptibility to all neuraminidase inhibitors of influenza H1N1 viruses with haemagglutinin mutations and mutations in non-conserved residues of the neuraminidase. J Antimicrob Chemother 68:2210 –2221. https://doi.org/10.1093/jac/dkt205.
69. McKimm-Breschkin JL. 2013. Influenza neuraminidase inhibitors: antiviral action and mechanisms of resistance. Influenza Other Respir Viruses 7(Suppl 1):S25–S36. https://doi.org/10.1111/irv.12047.
70. Stokes KL, Chi MH, Sakamoto K, Newcomb DC, Currier MG, Huckabee MM, Lee S, Goleniewska K, Pretto C, Williams JV, Hotard A, Sherrill TP, Peebles RS, Jr, Moore ML. 2011. Differential pathogenesis of respiratory syncytial virus clinical isolates in BALB/c mice. J Virol 85:5782–5793. https://doi.org/10.1128/JVI.01693-10.
71. Peebles RS, Jr, Graham BS. 2005. Pathogenesis of respiratory syncytial virus infection in the murine model. Proc Am Thorac Soc 2:110–115. https://doi.org/10.1513/pats.200501-002AW.
72. Belser JA, Wadford DA, Pappas C, Gustin KM, Maines TR, Pearce MB, Zeng H, Swayne DE, Pantin-Jackwood M, Katz JM, Tumpey TM. 2010. Pathogenesis of pandemic influenza A (H1N1) and triple-reassortant swine influenza A (H1) viruses in mice. J Virol 84:4194–4203. https://doi.org/ 10.1128/JVI.02742-09.
73. Belser JA, Lu X, Maines TR, Smith C, Li Y, Donis RO, Katz JM, Tumpey TM. 2007. Pathogenesis of avian influenza (H7) virus infection in mice and ferrets: enhanced virulence of Eurasian H7N7 viruses isolated from humans. J Virol 81:11139–11147. https://doi.org/10.1128/JVI.01235-07.
74. Yang YT, Evans CA. 1961. Hypothermia in mice due to influenza virus infection. Proc Soc Exp Biol Med 108:776–780. https://doi.org/10.3181/00379727-108-27064.
75. Sudo K, Watanabe W, Mori S, Konno K, Shigeta S, Yokota T. 1999. Mouse model of respiratory syncytial virus infection to evaluate antiviral activity in vivo. Antivir Chem Chemother 10:135–139. https://doi.org/10.1177/095632029901000305.
76. Mok CK, Lee HH, Chan MC, Sia SF, Lestra M, Nicholls JM, Zhu H, Guan Y, Peiris JM. 2013. Pathogenicity of the novel A/H7N9 influenza virus in mice. mBio 4:e00362-13. https://doi.org/10.1128/mBio.00362-13.
77. Kang YM, Song BM, Lee JS, Kim HS, Seo SH. 2011. Pandemic H1N1 influenza virus causes a stronger inflammatory response than seasonal H1N1 influenza virus in ferrets. Arch Virol 156:759–767. https://doi.org/10.1007/s00705-010-0914-7.
78. Hayden FG, Fritz R, Lobo MC, Alvord W, Strober W, Straus SE. 1998. Local and systemic cytokine responses during experimental human influenza A virus infection. Relation to symptom formation and host defense. J Clin Invest 101:643–649. https://doi.org/10.1172/JCI1355.
79. Paquette SG, Banner D, Zhao Z, Fang Y, Huang SS, Leomicronn AJ, Ng DC, Almansa R, Martin-Loeches I, Ramirez P, Socias L, Loza A, Blanco J, Sansonetti P, Rello J, Andaluz D, Shum B, Rubino S, de Lejarazu RO, Tran D, Delogu G, Fadda G, Krajden S, Rubin BB, Bermejo-Martin JF, Kelvin AA, Kelvin DJ. 2012. Interleukin-6 is a potential biomarker for severe pandemic H1N1 influenza A infection. PLoS One 7:e38214. https://doi.org/10.1371/journal.pone.0038214.
80. Killian ML. 2008. Hemagglutination assay for the avian influenza virus. Methods Mol Biol 436:47–52. https://doi.org/10.1007/978-1-59745-279-3_7.
81. National Research Council. 2011. Guide for the care and use of laboratory animals, 8th ed. National Academies Press, Washington, DC.
82. Razinkov V, Huntley C, Ellestad G, Krishnamurthy G. 2002. RSV entry inhibitors block F-protein mediated fusion with model membranes. Antiviral Res 55:189 –200. https://doi.org/10.1016/S0166-3542(02)00050-5.
83. Hampp C, Kauf TL, Saidi AS, Winterstein AG. 2012. Methodological concerns regarding cost-effectiveness analysis of palivizumab in Florida Medicaid—reply. Arch Pediatr Adolesc Med 166:968–970. https://doi.org/10.1001/archpediatrics.2012.1594.