Structural insights into HIV-1 Vif-APOBEC3F interaction

Journal of Virology

Volumn 90, Issue 2, 2016, Pages 1034-1047

  Nakashima, Masaaki ^a,b   Ode, Hirotaka ^a   Kawamura, Takashi ^b   Kitamura, Shingo ^a,b   Naganawa, Yuriko ^a   Awazu, Hiroaki ^a,b   Tsuzuki, Shinya ^a,b   Matsuoka, Kazuhiro ^a   Nemoto, Michiko ^a   Hachiya, Atsuko ^a   Sugiura, Wataru ^a,c   Yokomaku, Yoshiyuki ^a   Watanabe, Nobuhisa ^b   Iwatani, Yasumasa ^a,c  

^a NATIONAL HOSPITAL ORGANIZATION NAGOYA MEDICAL CENTER   (Japan)

^b NAGOYA UNIVERSITY   (Japan)

^c NAGOYA UNIVERSITY GRADUATE SCHOOL OF MEDICINE   (Japan)

Author keywords

[No Author keywords available]

Indexed keywords

APOLIPOPROTEIN B MESSENGER RNA EDITING ENZYME CATALYTIC POLYPEPTIDE 3F; VIF PROTEIN; APOBEC3C PROTEIN, HUMAN; APOBEC3F PROTEIN, HUMAN; CYTIDINE DEAMINASE; CYTOSINE DEAMINASE; VIF PROTEIN, HUMAN IMMUNODEFICIENCY VIRUS 1;

ALANINE SCANNING ANALYSIS; ANALYTIC METHOD; ARTICLE; CARBOXY TERMINAL SEQUENCE; CRYSTAL STRUCTURE; HUMAN IMMUNODEFICIENCY VIRUS 1; HYDROPHOBICITY; MODEL; NONHUMAN; PRIORITY JOURNAL; PROTEIN DEGRADATION; PROTEIN MOTIF; PROTEIN PROTEIN INTERACTION; PROTEIN STRUCTURE; STRUCTURE ACTIVITY RELATION; CHEMISTRY; DNA MUTATIONAL ANALYSIS; GENETICS; METABOLISM; MOLECULAR MODEL; PROTEIN ANALYSIS; PROTEIN CONFORMATION; SITE DIRECTED MUTAGENESIS; X RAY CRYSTALLOGRAPHY;

CRYSTALLOGRAPHY, X-RAY; CYTIDINE DEAMINASE; CYTOSINE DEAMINASE; DNA MUTATIONAL ANALYSIS; MODELS, MOLECULAR; MUTAGENESIS, SITE-DIRECTED; PROTEIN CONFORMATION; PROTEIN INTERACTION MAPPING; PROTEOLYSIS; VIF GENE PRODUCTS, HUMAN IMMUNODEFICIENCY VIRUS;

EID: 84954176012     PISSN: 0022538X     EISSN: 10985514     Source Type: Journal    
DOI: 10.1128/JVI.02369-15     Document Type: Article

References (71)

1. Albin JS, Harris RS. 2010. Interactions of host APOBEC3 restriction factors with HIV-1 in vivo: implications for therapeutics. Expert Rev Mol Med 12:e4. http://dx.doi.org/10.1017/S1462399409001343.
2. Desimmie BA, Delviks-Frankenberry KA, Burdick RC, Qi D, Izumi T, Pathak VK. 2014. Multiple APOBEC3 restriction factors for HIV-1 and one Vif to rule them all. J Mol Biol 426:1220-1245. http://dx.doi.org/10.1016/j.jmb.2013.10.033.
3. Goila-Gaur R, Strebel K. 2008. HIV-1 Vif, APOBEC, and intrinsic immunity. Retrovirology 5:51. http://dx.doi.org/10.1186/1742-4690-5-51.
4. Malim MH, Emerman M. 2008. HIV-1 accessory proteins-ensuring viral survival in a hostile environment. Cell Host Microbe 3:388-398. http://dx.doi.org/10.1016/j.chom.2008.04.008.
5. LaRue RS, Andresdottir V, Blanchard Y, Conticello SG, Derse D, Emerman M, Greene WC, Jonsson SR, Landau NR, Lochelt M, Malik HS, Malim MH, Munk C, O'Brien SJ, Pathak VK, Strebel K, Wain-Hobson S, Yu XF, Yuhki N, Harris RS. 2009. Guidelines for naming nonprimate APOBEC3 genes and proteins. J Virol 83:494-497. http://dx.doi.org/10.1128/JVI.01976-08.
6. Smith HC, Bennett RP, Kizilyer A, McDougall WM, Prohaska KM. 2012. Functions and regulation of the APOBEC family of proteins. Semin Cell Dev Biol 23:258-268. http://dx.doi.org/10.1016/j.semcdb.2011.10.004.
7. Dang Y, Siew LM, Wang X, Han Y, Lampen R, Zheng YH. 2008. Human cytidine deaminase APOBEC3H restricts HIV-1 replication. J Biol Chem 283:11606-11614. http://dx.doi.org/10.1074/jbc.M707586200.
8. Ooms M, Brayton B, Letko M, Maio SM, Pilcher CD, Hecht FM, Barbour JD, Simon V. 2013. HIV-1 Vif adaptation to human APOBEC3Hhaplotypes. Cell Host Microbe 14:411-421. http://dx.doi.org/10.1016/j.chom.2013.09.006.
9. Sheehy AM, Gaddis NC, Choi JD, Malim MH. 2002. Isolation of a human gene that inhibits HIV-1 infection and is suppressed by the viral Vif protein. Nature 418:646-650. http://dx.doi.org/10.1038/nature00939.
10. Wiegand HL, Doehle BP, Bogerd HP, Cullen BR. 2004. A second human antiretroviral factor, APOBEC3F, is suppressed by the HIV-1 and HIV-2 Vif proteins. EMBO J 23:2451-2458. http://dx.doi.org/10.1038/sj.emboj.7600246.
11. Zheng YH, Irwin D, Kurosu T, Tokunaga K, Sata T, Peterlin BM. 2004. Human APOBEC3F is another host factor that blocks human immunodeficiency virus type 1 replication. J Virol 78:6073-6076. http://dx.doi.org/10.1128/JVI.78.11.6073-6076.2004.
12. Iwatani Y, Takeuchi H, Strebel K, Levin JG. 2006. Biochemical activities of highly purified, catalytically active human APOBEC3G: correlation with antiviral effect. J Virol 80:5992-6002. http://dx.doi.org/10.1128/JVI.02680-05.
13. Iwatani Y, Chan DS, Wang F, Maynard KS, Sugiura W, Gronenborn AM, Rouzina I, Williams MC, Musier-Forsyth K, Levin JG. 2007. Deaminase-independent inhibition of HIV-1 reverse transcription by APOBEC3G. Nucleic Acids Res 35:7096-7108. http://dx.doi.org/10.1093/nar/gkm750.
14. Harris RS, Bishop KN, Sheehy AM, Craig HM, Petersen-Mahrt SK, Watt IN, Neuberger MS, Malim MH. 2003. DNA deamination mediates innate immunity to retroviral infection. Cell 113:803-809. http://dx.doi.org/10.1016/S0092-8674(03)00423-9.
15. Lecossier D, Bouchonnet F, Clavel F, Hance AJ. 2003. Hypermutation of HIV-1 DNA in the absence of the Vif protein. Science 300:1112. http://dx.doi.org/10.1126/science.1083338.
16. Mangeat B, Turelli P, Caron G, Friedli M, Perrin L, Trono D. 2003. Broad antiretroviral defence by human APOBEC3G through lethal editing of nascent reverse transcripts. Nature 424:99-103. http://dx.doi.org/10.1038/nature01709.
17. Zhang H, Yang B, Pomerantz RJ, Zhang C, Arunachalam SC, Gao L. 2003. The cytidine deaminase CEM15 induces hypermutation in newly synthesized HIV-1 DNA. Nature 424:94-98. http://dx.doi.org/10.1038/nature01707.
18. Bishop KN, Holmes RK, Malim MH. 2006. Antiviral potency of APOBEC proteins does not correlate with cytidine deamination. J Virol 80:8450-8458. http://dx.doi.org/10.1128/JVI.00839-06.
19. Newman EN, Holmes RK, Craig HM, Klein KC, Lingappa JR, Malim MH, Sheehy AM. 2005. Antiviral function of APOBEC3G can be dissociated from cytidine deaminase activity. Curr Biol 15:166-170. http://dx.doi.org/10.1016/j.cub.2004.12.068.
20. Chaurasiya KR, McCauley MJ, Wang W, Qualley DF, Wu T, Kitamura S, Geertsema H, Chan DS, Hertz A, Iwatani Y, Levin JG, Musier-Forsyth K, Rouzina I, Williams MC. 2014. Oligomerization transforms human APOBEC3G from an efficient enzyme to a slowly dissociating nucleic acid-binding protein. Nat Chem 6:28-33. http://dx.doi.org/10.1038/nchem.1795.
21. Yu X, Yu Y, Liu B, Luo K, Kong W, Mao P, Yu XF. 2003. Induction of APOBEC3G ubiquitination and degradation by an HIV-1 Vif-Cul5-SCF complex. Science 302:1056-1060. http://dx.doi.org/10.1126/science.1089591.
22. Jager S, Kim DY, Hultquist JF, Shindo K, LaRue RS, Kwon E, Li M, Anderson BD, Yen L, Stanley D, Mahon C, Kane J, Franks-Skiba K, Cimermancic P, Burlingame A, Sali A, Craik CS, Harris RS, Gross JD, Krogan NJ. 2012. Vif hijacks CBF-beta to degrade APOBEC3G and promote HIV-1 infection. Nature 481:371-375. http://dx.doi.org/10.1038/nature10693.
23. Zhang W, Du J, Evans SL, Yu Y, Yu XF. 2012. T-cell differentiation factor CBF-beta regulates HIV-1 Vif-mediated evasion of host restriction. Nature 481:376-379. http://dx.doi.org/10.1038/nature10718.
24. Kitamura S, Ode H, Iwatani Y. 2011. Structural features of antiviral APOBEC3 proteins are linked to their functional activities. Front Microbiol 2:258. http://dx.doi.org/10.3389/fmicb.2011.00258.
25. Aydin H, Taylor MW, Lee JE. 2014. Structure-guided analysis of the human APOBEC3-HIV restrictome. Structure 22:668-684. http://dx.doi.org/10.1016/j.str.2014.02.011.
26. Oberste MS, Gonda MA. 1992. Conservation of amino-acid sequence motifs in lentivirus Vif proteins. Virus Genes 6:95-102. http://dx.doi.org/10.1007/BF01703760.
27. Tian C, Yu X, Zhang W, Wang T, Xu R, Yu XF. 2006. Differential requirement for conserved tryptophans in human immunodeficiency virus type 1 Vif for the selective suppression of APOBEC3G and APOBEC3F. J Virol 80:3112-3115. http://dx.doi.org/10.1128/JVI.80.6.3112-3115.2006.
28. Schrofelbauer B, Senger T, Manning G, Landau NR. 2006. Mutational alteration of human immunodeficiency virus type 1 Vif allows for functional interaction with nonhuman primate APOBEC3G. J Virol 80:5984-5991. http://dx.doi.org/10.1128/JVI.00388-06.
29. Russell RA, Pathak VK. 2007. Identification of two distinct human immunodeficiency virus type 1 Vif determinants critical for interactions with human APOBEC3G and APOBEC3F. J Virol 81:8201-8210. http://dx.doi.org/10.1128/JVI.00395-07.
30. He Z, Zhang W, Chen G, Xu R, Yu XF. 2008. Characterization of conserved motifs in HIV-1 Vif required for APOBEC3G and APOBEC3F interaction. J Mol Biol 381:1000-1011. http://dx.doi.org/10.1016/j.jmb.2008.06.061.
31. Donahue JP, Vetter ML, Mukhtar NA, D'Aquila RT. 2008. The HIV-1 Vif PPLP motif is necessary for human APOBEC3G binding and degradation. Virology 377:49-53. http://dx.doi.org/10.1016/j.virol.2008.04.017.
32. Dang Y, Davis RW, York IA, Zheng YH. 2010. Identification of 81LGxGxxIxW89 and 171EDRW174 domains from human immunodeficiency virus type 1 Vif that regulate APOBEC3G and APOBEC3F neutralizing activity. J Virol 84:5741-5750. http://dx.doi.org/10.1128/JVI.00079-10.
33. Kitamura S, Ode H, Nakashima M, Imahashi M, Naganawa Y, Kurosawa T, Yokomaku Y, Yamane T, Watanabe N, Suzuki A, Sugiura W, Iwatani Y. 2012. The APOBEC3C crystal structure and the interface for HIV-1 Vif binding. Nat Struct Mol Biol 19:1005-1010. http://dx.doi.org/10.1038/nsmb.2378.
34. Albin JS, LaRue RS, Weaver JA, Brown WL, Shindo K, Harjes E, Matsuo H, Harris RS. 2010. A single amino acid in human APOBEC3F alters susceptibility to HIV-1 Vif. J Biol Chem 285:40785-40792. http://dx.doi.org/10.1074/jbc.M110.173161.
35. Nguyen K-L, Llano M, Akari H, Miyagi E, Poeschla EM, Strebel K, Bour S. 2004. Codon optimization of the HIV-1 vpu and vif genes stabilizes their mRNA and allows for highly efficient Rev-independent expression. Virology 319:163-175. http://dx.doi.org/10.1016/j.virol.2003.11.021.
36. Adachi A, Gendelman HE, Koenig S, Folks T, Willey R, Rabson A, Martin MA. 1986. Production of acquired immunodeficiency syndromeassociated retrovirus in human and nonhuman cells transfected with an infectious molecular clone. J Virol 59:284-291.
37. Kao S, Khan MA, Miyagi E, Plishka R, Buckler-White A, Strebel K. 2003. The human immunodeficiency virus type 1 Vif protein reduces intracellular expression and inhibits packaging of APOBEC3G (CEM15), a cellular inhibitor of virus infectivity. J Virol 77:11398-11407. http://dx.doi.org/10.1128/JVI.77.21.11398-11407.2003.
38. Wei X, Decker JM, Liu H, Zhang Z, Arani RB, Kilby JM, Saag MS, Wu X, Shaw GM, Kappes JC. 2002. Emergence of resistant human immunodeficiency virus type 1 in patients receiving fusion inhibitor (T-20) monotherapy. Antimicrob Agents Chemother 46:1896-1905. http://dx.doi.org/10.1128/AAC.46.6.1896-1905.2002.
39. Derdeyn CA, Decker JM, Sfakianos JN, Wu X, O'Brien WA, Ratner L, Kappes JC, Shaw GM, Hunter E. 2000. Sensitivity of human immunodeficiency virus type 1 to the fusion inhibitor T-20 is modulated by coreceptor specificity defined by the V3 loop of gp120. J Virol 74:8358-8367. http://dx.doi.org/10.1128/JVI.74.18.8358-8367.2000.
40. Takeuchi Y, McClure MO, Pizzato M. 2008. Identification of gammaretroviruses constitutively released from cell lines used for human immunodeficiency virus research. J Virol 82:12585-12588. http://dx.doi.org/10.1128/JVI.01726-08.
41. Platt EJ, Wehrly K, Kuhmann SE, Chesebro B, Kabat D. 1998. Effects of CCR5 and CD4 cell surface concentrations on infections by macrophagetropic isolates of human immunodeficiency virus type 1. J Virol 72:2855-2864.
42. Platt EJ, Bilska M, Kozak SL, Kabat D, Montefiori DC. 2009. Evidence that ecotropic murine leukemia virus contamination in TZM-bl cells does not affect the outcome of neutralizing antibody assays with human immunodeficiency virus type 1. J Virol 83:8289-8292. http://dx.doi.org/10.1128/JVI.00709-09.
43. Iwatani Y, Chan DS, Liu L, Yoshii H, Shibata J, Yamamoto N, Levin JG, Gronenborn AM, Sugiura W. 2009. HIV-1 Vif-mediated ubiquitination/degradation of APOBEC3G involves four critical lysine residues in its C-terminal domain. Proc Natl Acad SciUSA 106:19539-19544. http://dx.doi.org/10.1073/pnas.0906652106.
44. Otwinowski Z, Minor W. 1997. Processing of X-ray diffraction data collected in oscillation mode. Methods Enzymol 276:307-326. http://dx.doi.org/10.1016/S0076-6879(97)76066-X.
45. McCoy AJ, Grosse-Kunstleve RW, Adams PD, Winn MD, Storoni LC, Read RJ. 2007. Phaser crystallographic software. J Appl Crystallogr 40: 658-674. http://dx.doi.org/10.1107/S0021889807021206.
46. Winn MD, Ballard CC, Cowtan KD, Dodson EJ, Emsley P, Evans PR, Keegan RM, Krissinel EB, Leslie AG, McCoy A, McNicholas SJ, Murshudov GN, Pannu NS, Potterton EA, Powell HR, Read RJ, Vagin A, Wilson KS. 2011. Overview of the CCP4 suite and current developments. Acta Crystallogr D Biol Crystallogr 67:235-242. http://dx.doi.org/10.1107/S0907444910045749.
47. Vagin AA, Steiner RA, Lebedev AA, Potterton L, McNicholas S, Long F, Murshudov GN. 2004. REFMAC5 dictionary: organization of prior chemical knowledgeandguidelines for its use. Acta CrystallogrDBiol Crystallogr 60:2184-2195. http://dx.doi.org/10.1107/S0907444904023510.
48. Emsley P, Cowtan K. 2004. Coot: model-building tools for molecular graphics. Acta Crystallogr D Biol Crystallogr 60:2126-2132. http://dx.doi.org/10.1107/S0907444904019158.
49. Schrodinger LLC. 2010. The PyMOL molecular graphics system, version 1.6. Schrodinger, LLC, New York, NY.
50. Guo Y, Dong L, Qiu X, Wang Y, Zhang B, Liu H, Yu Y, Zang Y, Yang M, Huang Z. 2014. Structural basis for hijacking CBF-beta and CUL5 E3 ligase complex by HIV-1 Vif. Nature 505:229-233. http://dx.doi.org/10.1038/nature12884.
51. Sali A, Blundell TL. 1993. Comparative protein modelling by satisfaction of spatial restraints. J Mol Biol 234:779-815. http://dx.doi.org/10.1006/jmbi.1993.1626.
52. Case DA, Darden TA, Cheatham TEI, Simmerling CL, Wang J, Duke RE, Luo R, Merz KM, Pearlman DA, Crowley M, Walker RC, Zhang W, Wang B, Hayik S, Roitberg A, Seabra G, Wong KF, Paesani F, Wu X, Brozell S, Tsui V, Gohlke H, Yang L, Tan C, Mongan J, Hornak V, Cui G, Beroza P, Mathews DH, Schafmeister C, Ross WS, Kollman PA. 2006. AMBER 9. University of California, San Francisco, CA.
53. Pang YP, Xu K, Yazal JE, Prendergas FG. 2000. Successful molecular dynamics simulation of the zinc-bound farnesyltransferase using the cationic dummy atom approach. Protein Sci 9:1857-1865.
54. Schueler-Furman O, Wang C, Baker D. 2005. Progress in proteinprotein docking: atomic resolution predictions in the CAPRI experiment using RosettaDock with an improved treatment of side-chain flexibility. Proteins 60:187-194. http://dx.doi.org/10.1002/prot.20556.
55. Edgar RC. 2004. MUSCLE: multiple sequence alignment with high accuracy and high throughput. Nucleic Acids Res 32:1792-1797. http://dx.doi.org/10.1093/nar/gkh340.
56. Crooks GE, Hon G, Chandonia JM, Brenner SE. 2004. WebLogo: a sequence logo generator. Genome Res 14:1188-1190. http://dx.doi.org/10.1101/gr.849004.
57. Simon JH, Southerling TE, Peterson JC, Meyer BE, Malim MH. 1995. Complementation of vif-defective human immunodeficiency virus type 1 by primate, but not nonprimate, lentivirus vif genes. J Virol 69:4166-4172.
58. Bohn MF, Shandilya SM, Albin JS, Kouno T, Anderson BD, McDougle RM, Carpenter MA, Rathore A, Evans L, Davis AN, Zhang J, Lu Y, Somasundaran M, Matsuo H, Harris RS, Schiffer CA. 2013. Crystal structure of the DNA cytosine deaminase APOBEC3F: the catalytically active and HIV-1 Vif-binding domain. Structure 21:1042-1050. http://dx.doi.org/10.1016/j.str.2013.04.010.
59. Siu KK, Sultana A, Azimi FC, Lee JE. 2013. Structural determinants of HIV-1 Vif susceptibility and DNA binding in APOBEC3F. Nat Commun 4:2593. http://dx.doi.org/10.1038/ncomms3593.
60. Holmes RK, Koning FA, Bishop KN, Malim MH. 2007. APOBEC3F can inhibit the accumulation of HIV-1 reverse transcription products in the absence of hypermutation. Comparisons with APOBEC3G. J Biol Chem 282:2587-2595.
61. Byeon IJ, Ahn J, Mitra M, Byeon CH, Hercik K, Hritz J, Charlton LM, Levin JG, Gronenborn AM. 2013. NMR structure of human restriction factor APOBEC3A reveals substrate binding and enzyme specificity. Nat Commun 4:1890. http://dx.doi.org/10.1038/ncomms2883.
62. Shandilya SM, Nalam MN, Nalivaika EA, Gross PJ, Valesano JC, Shindo K, Li M, Munson M, Royer WE, Harjes E, Kono T, Matsuo H, Harris RS, Somasundaran M, Schiffer CA. 2010. Crystal structure of the APOBEC3G catalytic domain reveals potential oligomerization interfaces. Structure 18:28-38. http://dx.doi.org/10.1016/j.str.2009.10.016.
63. Etienne L, Hahn BH, Sharp PM, Matsen FA, Emerman M. 2013. Gene loss and adaptation to hominids underlie the ancient origin of HIV-1. Cell Host Microbe 14:85-92. http://dx.doi.org/10.1016/j.chom.2013.06.002.
64. Yu Q, Chen D, Konig R, Mariani R, Unutmaz D, Landau NR. 2004. APOBEC3B and APOBEC3C are potent inhibitors of simian immunodeficiency virus replication. J Biol Chem 279:53379-53386. http://dx.doi.org/10.1074/jbc.M408802200.
65. Hultquist JF, Lengyel JA, Refsland EW, LaRue RS, Lackey L, Brown WL, Harris RS. 2011. Human and rhesus APOBEC3D, APOBEC3F, APOBEC3G, and APOBEC3H demonstrate a conserved capacity to restrict Vif-deficient HIV-1. J Virol 85:11220-11234. http://dx.doi.org/10.1128/JVI.05238-11.
66. Duggal NK, Malik HS, Emerman M. 2011. The breadth of antiviral activity of Apobec3DE in chimpanzees has been driven by positive selection. J Virol 85:11361-11371. http://dx.doi.org/10.1128/JVI.05046-11.
67. Smith JL, Pathak VK. 2010. Identification of specific determinants of human APOBEC3F, APOBEC3C, and APOBEC3DE and African green monkey APOBEC3F that interact with HIV-1 Vif. J Virol 84:12599-12608. http://dx.doi.org/10.1128/JVI.01437-10.
68. Land AM, Shaban NM, Evans L, Hultquist JF, Albin JS, Harris RS. 2014. APOBEC3F determinants of HIV-1 Vif sensitivity. J Virol 88:12923-12927. http://dx.doi.org/10.1128/JVI.02362-14.
69. Prado-Martinez J, Sudmant PH, Kidd JM, Li H, Kelley JL, Lorente-Galdos B, Veeramah KR, Woerner AE, O'Connor TD, Santpere G, Cagan A, Theunert C, Casals F, Laayouni H, Munch K, Hobolth A, Halager AE, Malig M, Hernandez-Rodriguez J, Hernando-Herraez I, Prufer K, Pybus M, Johnstone L, Lachmann M, Alkan C, Twigg D, Petit N, Baker C, Hormozdiari F, Fernandez-Callejo M, Dabad M, Wilson ML, Stevison L, Camprubi C, Carvalho T, Ruiz-Herrera A, Vives L, Mele M, Abello T, Kondova I, Bontrop RE, Pusey A, Lankester F, Kiyang JA, Bergl RA, Lonsdorf E, Myers S, Ventura M, Gagneux P, Comas D, et al. 2013. Great ape genetic diversity and population history. Nature 499:471-475. http://dx.doi.org/10.1038/nature12228.
70. Gao F, Bailes E, Robertson DL, Chen Y, Rodenburg CM, Michael SF, Cummins LB, Arthur LO, Peeters M, Shaw GM, Sharp PM, Hahn BH. 1999. Origin of HIV-1 in the chimpanzee Pan troglodytes troglodytes. Nature 397:436-441. http://dx.doi.org/10.1038/17130.
71. SharpPM,HahnBH. 2011. Origins ofHIVandtheAIDSpandemic. ColdSpring Harb Perspect Med 1:a006841. http://dx.doi.org/10.1101/cshperspect.a006841.