Experimental Estimation of the Effects of All Amino-Acid Mutations to HIV’s Envelope Protein on Viral Replication in Cell Culture

PLoS Pathogens

Volumn 12, Issue 12, 2016, Pages

  Haddox, Hugh K ^a,b   Dingens, Adam S ^a,b   Bloom, Jesse D ^a  

^a USA   (United States)

^b UNIVERSITY OF WASHINGTON   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CD4 ANTIGEN; GLYCOPROTEIN GP 120; VIRUS ENVELOPE PROTEIN; NEUTRALIZING ANTIBODY; VIRUS ANTIBODY;

AMINO ACID SEQUENCE; ARTICLE; CELL CULTURE; CONTROLLED STUDY; GENE MUTATION; GENE SEQUENCE; GENOTYPE PHENOTYPE CORRELATION; HUMAN IMMUNODEFICIENCY VIRUS; MUTAGENESIS; NONHUMAN; POLYMERASE CHAIN REACTION; PROTEIN BINDING; VIRUS REPLICATION; GENETICS; HEK293 CELL LINE; HIGH THROUGHPUT SEQUENCING; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS 1; IMMUNOLOGY; MOLECULAR GENETICS; MUTATION; PROCEDURES;

AMINO ACID SEQUENCE; ANTIBODIES, NEUTRALIZING; ANTIBODIES, VIRAL; ENV GENE PRODUCTS, HUMAN IMMUNODEFICIENCY VIRUS; HEK293 CELLS; HIGH-THROUGHPUT NUCLEOTIDE SEQUENCING; HIV-1; HUMANS; MOLECULAR SEQUENCE DATA; MUTATION; POLYMERASE CHAIN REACTION; VIRUS REPLICATION;

EID: 85008164772     PISSN: 15537366     EISSN: 15537374     Source Type: Journal    
DOI: 10.1371/journal.ppat.1006114     Document Type: Article

References (135)

1. Zanini F, Brodin J, Thebo L, Lanz C, Bratt G, Albert J, et al. Population genomics of intrapatient HIV-1 evolution. eLife. 2015;4:e11282. doi: 10.7554/eLife.1128226652000
2. Chen FC, Vallender E, Wang H, Tzeng CS, Li WH, Genomic divergence between human and chimpanzee estimated from large-scale alignments of genomic sequences. Journal of Heredity. 2001;92(6):481–489. doi: 10.1093/jhered/92.6.48111948215
3. Mikkelsen T, Hillier L, Eichler E, Zody M, Jaffe D, Yang SP, et al. Initial sequence of the chimpanzee genome and comparison with the human genome. Nature. 2005;437(7055):69–87. doi: 10.1038/nature04072
4. Langergraber KE, Prüfer K, Rowney C, Boesch C, Crockford C, Fawcett K, et al. Generation times in wild chimpanzees and gorillas suggest earlier divergence times in great ape and human evolution. Proceedings of the National Academy of Sciences. 2012;109(39):15716–15721. doi: 10.1073/pnas.1211740109
5. Albert J, Abrahamsson B, Nagy K, Aurelius E, Gaines H, Nyström G, et al. Rapid development of isolate-specific neutralizing antibodies after primary HIV-1 infection and consequent emergence of virus variants which resist neutralization by autologous sera. Aids. 1990;4(2):107–112. doi: 10.1097/00002030-199002000-000022328092
6. Wei X, Decker JM, Wang S, Hui H, Kappes JC, Wu X, et al. Antibody neutralization and escape by HIV-1. Nature. 2003;422(6929):307–312. doi: 10.1038/nature0147012646921
7. Richman DD, Wrin T, Little SJ, Petropoulos CJ, Rapid evolution of the neutralizing antibody response to HIV type 1 infection. Proceedings of the National Academy of Sciences. 2003;100(7):4144–4149. doi: 10.1073/pnas.0630530100
8. Olshevsky U, Helseth E, Furman C, Li J, Haseltine W, Sodroski J, Identification of individual human immunodeficiency virus type 1 gp120 amino acids important for CD4 receptor binding. Journal of virology. 1990;64(12):5701–5707. 2243375
9. Cordonnier A, Montagnier L, Emerman M, Single amino-acid changes in HIV envelope affect viral tropism and receptor binding. Nature. 1989;340(6234):571. doi: 10.1038/340571a02475780
10. Basmaciogullari S, Babcock GJ, Van Ryk D, Wojtowicz W, Sodroski J, Identification of conserved and variable structures in the human immunodeficiency virus gp120 glycoprotein of importance for CXCR4 binding. Journal of virology. 2002;76(21):10791–10800. doi: 10.1128/JVI.76.21.10791-10800.200212368322
11. Freed E, Myers D, Risser R, Mutational analysis of the cleavage sequence of the human immunodeficiency virus type 1 envelope glycoprotein precursor gp160. Journal of virology. 1989;63(11):4670–4675. 2677400
12. Lu M, Stoller MO, Wang S, Liu J, Fagan MB, Nunberg JH, Structural and functional analysis of interhelical interactions in the human immunodeficiency virus type 1 gp41 envelope glycoprotein by alanine-scanning mutagenesis. Journal of virology. 2001;75(22):11146–11156. doi: 10.1128/JVI.75.22.11146-11156.200111602754
13. Jacobs A, Sen J, Rong L, Caffrey M, Alanine scanning mutants of the HIV gp41 loop. Journal of Biological Chemistry. 2005;280(29):27284–27288. doi: 10.1074/jbc.M41441120015917239
14. Zwick MB, Jensen R, Church S, Wang M, Stiegler G, Kunert R, et al. Anti-human immunodeficiency virus type 1 (HIV-1) antibodies 2F5 and 4E10 require surprisingly few crucial residues in the membrane-proximal external region of glycoprotein gp41 to neutralize HIV-1. Journal of virology. 2005;79(2):1252–1261. doi: 10.1128/JVI.79.2.1252-1261.200515613352
15. Pantophlet R, Saphire EO, Poignard P, Parren PW, Wilson IA, Burton DR, Fine mapping of the interaction of neutralizing and nonneutralizing monoclonal antibodies with the CD4 binding site of human immunodeficiency virus type 1 gp120. Journal of virology. 2003;77(1):642–658. doi: 10.1128/JVI.77.1.642-658.200312477867
16. Li Y, O’Dell S, Walker LM, Wu X, Guenaga J, Feng Y, et al. Mechanism of neutralization by the broadly neutralizing HIV-1 monoclonal antibody VRC01. Journal of virology. 2011;85(17):8954–8967. doi: 10.1128/JVI.00754-1121715490
17. Lynch RM, Wong P, Tran L, O’Dell S, Nason MC, Li Y, et al. HIV-1 fitness cost associated with escape from the VRC01 class of CD4 binding site neutralizing antibodies. Journal of virology. 2015;89(8):4201–4213. doi: 10.1128/JVI.03608-1425631091
18. Dahirel V, Shekhar K, Pereyra F, Miura T, Artyomov M, Talsania S, et al. Coordinate linkage of HIV evolution reveals regions of immunological vulnerability. Proceedings of the National Academy of Sciences. 2011;108(28):11530–11535. doi: 10.1073/pnas.1105315108
19. Ferguson AL, Mann JK, Omarjee S, Ndung’u T, Walker BD, Chakraborty AK, Translating HIV sequences into quantitative fitness landscapes predicts viral vulnerabilities for rational immunogen design. Immunity. 2013;38(3):606–617. doi: 10.1016/j.immuni.2012.11.02223521886
20. Zanini F, Puller V, Brodin J, Albert J, Neher R, In-vivo mutation rates and fitness landscape of HIV-1. arXiv preprint arXiv:160306634. 2016;.
21. Zanini F, Neher RA, Quantifying selection against synonymous mutations in HIV-1 env evolution. Journal of virology. 2013;87(21):11843–11850. doi: 10.1128/JVI.01529-1323986591
22. Hartl, M, Theys, K, Feder, A, Gelbart, M, Stern, A, Pennings, PS. Within-patient HIV mutation frequencies reveal fitness costs of CpG dinucleotides, drastic amino acid changes and G→A mutations. bioRxiv. 2016; p. 057026.
23. Fowler DM, Araya CL, Fleishman SJ, Kellogg EH, Stephany JJ, Baker D, et al. High-resolution mapping of protein sequence-function relationships. Nature methods. 2010;7(9):741–746. doi: 10.1038/nmeth.149220711194
24. Fowler DM, Fields S, Deep mutational scanning: a new style of protein science. Nature methods. 2014;11(8):801–807. doi: 10.1038/nmeth.302725075907
25. Boucher JI, Cote P, Flynn J, Jiang L, Laban A, Mishra P, et al. Viewing protein fitness landscapes through a next-gen lens. Genetics. 2014;198(2):461–471. doi: 10.1534/genetics.114.16835125316787
26. McLaughlin RN, JrPoelwijk FJ, Raman A, Gosal WS, Ranganathan R, The spatial architecture of protein function and adaptation. Nature. 2012;491(7422):138–142. doi: 10.1038/nature11500
27. Roscoe BP, Thayer KM, Zeldovich KB, Fushman D, Bolon DN, Analyses of the effects of all ubiquitin point mutants on yeast growth rate. Journal of molecular biology. 2013;425(8):1363–1377. doi: 10.1016/j.jmb.2013.01.03223376099
28. Firnberg E, Labonte JW, Gray JJ, Ostermeier M, A comprehensive, high-resolution map of a gene’s fitness landscape. Molecular biology and evolution. 2014;31(6):1581–1592. doi: 10.1093/molbev/msu08124567513
29. Olson CA, Wu NC, Sun R, A comprehensive biophysical description of pairwise epistasis throughout an entire protein domain. Current Biology. 2014;24(22):2643–2651. doi: 10.1016/j.cub.2014.09.07225455030
30. Melnikov A, Rogov P, Wang L, Gnirke A, Mikkelsen TS, Comprehensive mutational scanning of a kinase in vivo reveals substrate-dependent fitness landscapes. Nucleic Acids Research. 2014;42(14):e112. doi: 10.1093/nar/gku51124914046
31. Bloom JD, An Experimentally Determined Evolutionary Model Dramatically Improves Phylogenetic Fit. Mol Biol Evol. 2014;31(8):1956–1978. doi: 10.1093/molbev/msu17324859245
32. Qi H, Olson CA, Wu NC, Ke R, Loverdo C, Chu V, et al. A quantitative high-resolution genetic profile rapidly identifies sequence determinants of hepatitis C viral fitness and drug sensitivity. PLoS Pathog. 2014;10(4):e1004064. doi: 10.1371/journal.ppat.100406424722365
33. Thyagarajan B, Bloom JD, The inherent mutational tolerance and antigenic evolvability of influenza hemagglutinin. eLife. 2014;3:e03300. doi: 10.7554/eLife.03300
34. Stiffler MA, Hekstra DR, Ranganathan R, Evolvability as a function of purifying selection in TEM-1β-lactamase. Cell. 2015;160(5):882–892. doi: 10.1016/j.cell.2015.01.03525723163
35. Doud M, Ashenberg O, Bloom J, Site-Specific Amino Acid Preferences Are Mostly Conserved in Two Closely Related Protein Homologs. Molecular biology and evolution. 2015;32(11):2944–2960. doi: 10.1093/molbev/msv16726226986
36. Kitzman JO, Starita LM, Lo RS, Fields S, Shendure J, Massively parallel single-amino-acid mutagenesis. Nature methods. 2015;12(3):203–206. doi: 10.1038/nmeth.322325559584
37. Mishra P, Flynn JM, Starr TN, Bolon DN, Systematic Mutant Analyses Elucidate General and Client-Specific Aspects of Hsp90 Function. Cell reports. 2016;15(3):588–598. doi: 10.1016/j.celrep.2016.03.04627068472
38. Doud MB, Bloom JD, Accurate measurement of the effects of all amino-acid mutations to influenza hemagglutinin. Viruses. 2016;8:155. doi: 10.3390/v8060155
39. Mavor D, Fraser J, et al. Determination of Ubiquitin Fitness Landscapes Under Different Chemical Stresses in a Classroom Setting. eLife. 2016;5:e15802. doi: 10.7554/eLife.1580227111525
40. Wu NC, Young AP, Al-Mawsawi LQ, Olson CA, Feng J, Qi H, et al. High-throughput profiling of influenza A virus hemagglutinin gene at single-nucleotide resolution. Scientific reports. 2014;4:4942. doi: 10.1038/srep0494224820965
41. Starita LM, Young DL, Islam M, Kitzman JO, Gullingsrud J, Hause RJ, et al. Massively parallel functional analysis of BRCA1 RING domain variants. Genetics. 2015;200(2):413–422. doi: 10.1534/genetics.115.17580225823446
42. Wu NC, Olson CA, Du Y, Le S, Tran K, Remenyi R, et al. Functional constraint profiling of a viral protein reveals discordance of evolutionary conservation and functionality. PLoS Genet. 2015;11(7):e1005310. doi: 10.1371/journal.pgen.100531026132554
43. Steichen JM, Kulp DW, Tokatlian T, Escolano A, Dosenovic P, Stanfield RL, et al. HIV vaccine design to target germline precursors of glycan-dependent broadly neutralizing antibodies. Immunity. 2016;45(3):483–496. doi: 10.1016/j.immuni.2016.08.01627617678
44. Jardine JG, Kulp DW, Havenar-Daughton C, Sarkar A, Briney B, Sok D, et al. HIV-1 broadly neutralizing antibody precursor B cells revealed by germline-targeting immunogen. Science. 2016;351(6280):1458–1463. doi: 10.1126/science.aad919527013733
45. Al-Mawsawi LQ, Wu NC, Olson C, Shi VC, Qi H, Zheng X, et al. High-throughput profiling of point mutations across the HIV-1 genome. Retrovirology. 2014;11(1):124. doi: 10.1186/s12977-014-0124-625522661
46. Peden K, Emerman M, Montagnier L, Changes in growth properties on passage in tissue culture of viruses derived from infectious molecular clones of HIV-1 LAI, HIV-1 MAL, and HIV-1 ELI. Virology. 1991;185(2):661–672. doi: 10.1016/0042-6822(91)90537-L1683726
47. Kwong PD, Wyatt R, Robinson J, Sweet RW, Sodroski J, Hendrickson WA, Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody. Nature. 1998;393(6686):648–659. doi: 10.1038/314059641677
48. Pancera M, Majeed S, Ban YEA, Chen L, Huang Cc, Kong L, et al. Structure of HIV-1 gp120 with gp41-interactive region reveals layered envelope architecture and basis of conformational mobility. Proceedings of the National Academy of Sciences. 2010;107(3):1166–1171. doi: 10.1073/pnas.0911004107
49. van Anken E, Sanders RW, Liscaljet IM, Land A, Bontjer I, Tillemans S, et al. Only five of 10 strictly conserved disulfide bonds are essential for folding and eight for function of the HIV-1 envelope glycoprotein. Molecular biology of the cell. 2008;19(10):4298–4309. doi: 10.1091/mbc.E07-12-128218653472
50. Korber B, Foley BT, Kuiken C, Pillai SK, Sodroski JG, et al. Numbering positions in HIV relative to HXB2CG. Human retroviruses and AIDS. 1998;3:102–111.
51. Chakrabarti L, Emerman M, Tiollais P, Sonigo P, The cytoplasmic domain of simian immunodeficiency virus transmembrane protein modulates infectivity. Journal of virology. 1989;63(10):4395–4403. 2778881
52. Yuste E, Reeves JD, Doms RW, Desrosiers RC, Modulation of Env content in virions of simian immunodeficiency virus: correlation with cell surface expression and virion infectivity. Journal of virology. 2004;78(13):6775–6785. doi: 10.1128/JVI.78.13.6775-6785.200415194752
53. Li Y, Luo L, Thomas DY, Kang OY, Control of expression, glycosylation, and secretion of HIV-1 gp120 by homologous and heterologous signal sequences. Virology. 1994;204(1):266–278. doi: 10.1006/viro.1994.15318091657
54. Sheehy AM, Gaddis NC, Choi JD, Malim MH, Isolation of a human gene that inhibits HIV-1 infection and is suppressed by the viral Vif protein. Nature. 2002;418(6898):646–650. doi: 10.1038/nature0093912167863
55. Refsland EW, Stenglein MD, Shindo K, Albin JS, Brown WL, Harris RS, Quantitative profiling of the full APOBEC3 mRNA repertoire in lymphocytes and tissues: implications for HIV-1 restriction. Nucleic acids research. 2010;38(13):4274–4284. doi: 10.1093/nar/gkq17420308164
56. Ho YC, Shan L, Hosmane NN, Wang J, Laskey SB, Rosenbloom DI, et al. Replication-competent noninduced proviruses in the latent reservoir increase barrier to HIV-1 cure. Cell. 2013;155(3):540–551. doi: 10.1016/j.cell.2013.09.02024243014
57. Cuevas JM, Geller R, Garijo R, López-Aldeguer J, Sanjuán R, Extremely High Mutation Rate of HIV-1 In Vivo. PLoS Biol. 2015;13(9):e1002251. doi: 10.1371/journal.pbio.100225126375597
58. Hiatt JB, Patwardhan RP, Turner EH, Lee C, Shendure J, Parallel, tag-directed assembly of locally derived short sequence reads. Nat Methods. 2010;7(2):119–122. doi: 10.1038/nmeth.141620081835
59. Jabara CB, Jones CD, Roach J, Anderson JA, Swanstrom R, Accurate sampling and deep sequencing of the HIV-1 protease gene using a Primer ID. Proceedings of the National Academy of Sciences. 2011;108(50):20166–20171. doi: 10.1073/pnas.1110064108
60. Kinde I, Wu J, Papadopoulos N, Kinzler KW, Vogelstein B, Detection and quantification of rare mutations with massively parallel sequencing. Proceedings of the National Academy of Sciences. 2011;108(23):9530–9535. doi: 10.1073/pnas.1105422108
61. Zhang TH, Wu NC, Sun R, A benchmark study on error-correction by read-pairing and tag-clustering in amplicon-based deep sequencing. BMC genomics. 2016;17(1):1. doi: 10.1186/s12864-016-2388-9
62. Sloan RD, Wainberg MA, The role of unintegrated DNA in HIV infection. Retrovirology. 2011;8(1):1. doi: 10.1186/1742-4690-8-52
63. Guo HH, Choe J, Loeb LA, Protein tolerance to random amino acid change. Proceedings of the National Academy of Sciences of the United States of America. 2004;101(25):9205–9210. doi: 10.1073/pnas.040325510115197260
64. Shafikhani S, Siegel R, Ferrari E, Schellenberger V, Generation of large libraries of random mutants in Bacillus subtilis by PCR-based plasmid multimerization. Biotechniques. 1997;23(2):304–311. 9266088
65. Bloom JD, Silberg JJ, Wilke CO, Drummond DA, Adami C, Arnold FH, Thermodynamic prediction of protein neutrality. Proceedings of the National Academy of Sciences of the United States of America. 2005;102(3):606–611. doi: 10.1073/pnas.040674410215644440
66. Johnson WE, Desrosiers RC, Viral persistence: HIV’s strategies of immune system evasion. Annual review of medicine. 2002;53(1):499–518. doi: 10.1146/annurev.med.53.082901.10405311818487
67. Ohgimoto S, Shioda T, Mori K, Nakayama EE, Hu H, Nagai Y, Location-specific, unequal contribution of the N glycans in simian immunodeficiency virus gp120 to viral infectivity and removal of multiple glycans without disturbing infectivity. Journal of virology. 1998;72(10):8365–8370. 9733886
68. Pugach P, Kuhmann SE, Taylor J, Marozsan AJ, Snyder A, Ketas T, et al. The prolonged culture of human immunodeficiency virus type 1 in primary lymphocytes increases its sensitivity to neutralization by soluble CD4. Virology. 2004;321(1):8–22. doi: 10.1016/j.virol.2003.12.01215033560
69. Wang W, Nie J, Prochnow C, Truong C, Jia Z, Wang S, et al. A systematic study of the N-glycosylation sites of HIV-1 envelope protein on infectivity and antibody-mediated neutralization. Retrovirology. 2013;10(1):1. doi: 10.1186/1742-4690-10-14
70. Moore JP, Cao Y, Qing L, Sattentau QJ, Pyati J, Koduri R, et al. Primary isolates of human immunodeficiency virus type 1 are relatively resistant to neutralization by monoclonal antibodies to gp120, and their neutralization is not predicted by studies with monomeric gp120. Journal of virology. 1995;69(1):101–109. 7527081
71. Sullivan N, Sun Y, Li J, Hofmann W, Sodroski J, Replicative function and neutralization sensitivity of envelope glycoproteins from primary and T-cell line-passaged human immunodeficiency virus type 1 isolates. Journal of virology. 1995;69(7):4413–4422. 7769703
72. Guttman M, Cupo A, Julien JP, Sanders RW, Wilson IA, Moore JP, et al. Antibody potency relates to the ability to recognize the closed, pre-fusion form of HIV Env. Nature communications. 2015;6. doi: 10.1038/ncomms714425652336
73. Stewart-Jones GB, Soto C, Lemmin T, Chuang GY, Druz A, Kong R, et al. Trimeric HIV-1-Env Structures Define Glycan Shields from Clades A, B, and G. Cell. 2016;165(4):813–826. doi: 10.1016/j.cell.2016.04.01027114034
74. Sanders RW, Vesanen M, Schuelke N, Master A, Schiffner L, Kalyanaraman R, et al. Stabilization of the soluble, cleaved, trimeric form of the envelope glycoprotein complex of human immunodeficiency virus type 1. Journal of virology. 2002;76(17):8875–8889. doi: 10.1128/JVI.76.17.8875-8889.200212163607
75. de Taeye SW, Ozorowski G, de la Peña AT, Guttman M, Julien JP, van den Kerkhof TL, et al. Immunogenicity of Stabilized HIV-1 Envelope Trimers with Reduced Exposure of Non-neutralizing Epitopes. Cell. 2015;163(7):1702–1715. doi: 10.1016/j.cell.2015.11.05626687358
76. Rizzuto CD, Wyatt R, Hernández-Ramos N, Sun Y, Kwong PD, Hendrickson WA, et al. A conserved HIV gp120 glycoprotein structure involved in chemokine receptor binding. Science. 1998;280(5371):1949–1953. doi: 10.1126/science.280.5371.19499632396
77. Wain-Hobson S, Vartanian JP, Henry M, Chenciner N, Cheynier R, Delassus S, et al. LAV revisited: origins of the early HIV-1 isolates from Institut Pasteur. Science. 1991;252(5008):961–965. doi: 10.1126/science.20350262035026
78. Shaw GM, Arya BHHSK, Molecular Characterization of Human T-Cell Leukemia (Lymphotropic) Virus Type III in the Acquired Immune Deficiency Syndrome. Science l984. 1984;226:l.
79. Chang SYP, Bowman BH, Weiss JB, Garcia RE, White TJ, The origin of HIV-1 isolate HTLV-IIIB. Nature. 1993;363(6428):466–469. doi: 10.1038/363466a08502298
80. Parmley JL, Chamary J, Hurst LD, Evidence for purifying selection against synonymous mutations in mammalian exonic splicing enhancers. Molecular biology and evolution. 2006;23(2):301–309.
81. Cuevas JM, Domingo-Calap P, Sanjuán R, The Fitness Effects of Synonymous Mutations in DNA and RNA Viruses. Molecular Biology and Evolution. 2012;29(1):17–20. doi: 10.1093/molbev/msr17921771719
82. Subramaniam AR, DeLoughery A, Bradshaw N, Chen Y, O’Shea E, Losick R, et al. A serine sensor for multicellularity in a bacterium. Elife. 2013;2:e01501. doi: 10.7554/eLife.0150124347549
83. Haas J, Park EC, Seed B, Codon usage limitation in the expression of HIV-1 envelope glycoprotein. Current Biology. 1996;6(3):315–324. doi: 10.1016/S0960-9822(02)00482-78805248
84. Watts JM, Dang KK, Gorelick RJ, Leonard CW, Bess JW, JrSwanstrom R, et al. Architecture and secondary structure of an entire HIV-1 RNA genome. Nature. 2009;460(7256):711–716. doi: 10.1038/nature0823719661910
85. Fernandes J, Jayaraman B, Frankel A, The HIV-1 Rev response element: an RNA scaffold that directs the cooperative assembly of a homo-oligomeric ribonucleoprotein complex. RNA biology. 2012;9(1):6–11. doi: 10.4161/rna.9.1.1817822258145
86. Malim MH, Hauber J, Le SY, Maizel JV, Cullen BR, The HIV-1 rev trans-activator acts through a structured target sequence to activate nuclear export of unspliced viral mRNA. Nature. 1989;338(6212):254–257. doi: 10.1038/338254a02784194
87. Emerman M, Vazeux R, Peden K, The rev gene product of the human immunodeficiency virus affects envelope-specific RNA localization. Cell. 1989;57(7):1155–1165. doi: 10.1016/0092-8674(89)90053-62736624
88. Bloom JD, Software for the analysis and visualization of deep mutational scanning data. BMC bioinformatics. 2015;16:168. doi: 10.1186/s12859-015-0590-425990960
89. Bloom JD, An experimentally informed evolutionary model improves phylogenetic fit to divergent lactamase homologs. Molecular biology and evolution. 2014;31(10):2753–2769. doi: 10.1093/molbev/msu22025063439
90. Kyte J, Doolittle RF, A simple method for displaying the hydropathic character of a protein. Journal of molecular biology. 1982;157(1):105–132. doi: 10.1016/0022-2836(82)90515-07108955
91. Bloom JD, Identification of positive selection in genes is greatly improved by using experimentally informed site-specific models. bioRxiv. 2016; p. 037689.
92. Weinreich DM, Delaney NF, DePristo MA, Hartl DL, Darwinian evolution can follow only very few mutational paths to fitter proteins. science. 2006;312(5770):111–114. doi: 10.1126/science.112353916601193
93. Ortlund EA, Bridgham JT, Redinbo MR, Thornton JW, Crystal structure of an ancient protein: evolution by conformational epistasis. Science. 2007;317(5844):1544–1548. doi: 10.1126/science.114281917702911
94. Freed E, Martin M, Evidence for a functional interaction between the V1/V2 and C4 domains of human immunodeficiency virus type 1 envelope glycoprotein gp120. Journal of virology. 1994;68(4):2503–2512. 8139032
95. Wang WK, Essex M, Lee TH, Single amino acid substitution in constant region 1 or 4 of gp120 causes the phenotype of a human immunodeficiency virus type 1 variant with mutations in hypervariable regions 1 and 2 to revert. Journal of virology. 1996;70(1):607–611. 8523579
96. da Silva J, Coetzer M, Nedellec R, Pastore C, Mosier DE, Fitness epistasis and constraints on adaptation in a human immunodeficiency virus type 1 protein region. Genetics. 2010;185(1):293–303. doi: 10.1534/genetics.109.11245820157005
97. Gasser R, Hamoudi M, Pellicciotta M, Zhou Z, Visdeloup C, Colin P, et al. Buffering deleterious polymorphisms in highly constrained parts of HIV-1 envelope by flexible regions. Retrovirology. 2016;13(1):50. doi: 10.1186/s12977-016-0285-627473399
98. Abram ME, Ferris AL, Shao W, Alvord WG, Hughes SH, Nature, position, and frequency of mutations made in a single cycle of HIV-1 replication. Journal of virology. 2010;84(19):9864–9878. doi: 10.1128/JVI.00915-1020660205
99. Spielman SJ, Wilke CO, Pyvolve: a flexible Python module for simulating sequences along phylogenies. PloS one. 2015;10(9):e0139047. doi: 10.1371/journal.pone.013904726397960
100. Nielsen R, Yang Z, Likelihood models for detecting positively selected amino acid sites and applications to the HIV-1 envelope gene. Genetics. 1998;148(3):929–936. 9539414
101. Shankarappa R, Margolick JB, Gange SJ, Rodrigo AG, Upchurch D, Farzadegan H, et al. Consistent viral evolutionary changes associated with the progression of human immunodeficiency virus type 1 infection. Journal of virology. 1999;73(12):10489–10502. 10559367
102. Overbaugh J, Morris L, The antibody response against HIV-1. Cold Spring Harbor perspectives in medicine. 2012;2(1):a007039. doi: 10.1101/cshperspect.a00703922315717
103. Lee WR, Syu WJ, Du B, Matsuda M, Tan S, Wolf A, et al. Nonrandom distribution of gp120 N-linked glycosylation sites important for infectivity of human immunodeficiency virus type 1. Proceedings of the National Academy of Sciences. 1992;89(6):2213–2217. doi: 10.1073/pnas.89.6.2213
104. Meyer AG, Wilke CO, The utility of protein structure as a predictor of site-wise dN/dS varies widely among HIV-1 proteins. Journal of The Royal Society Interface. 2015;12(111):20150579. doi: 10.1098/rsif.2015.0579
105. Starcich BR, Hahn BH, Shaw GM, McNeely PD, Modrow S, Wolf H, et al. Identification and characterization of conserved and variable regions in the envelope gene of HTLV-III/LAV, the retrovirus of AIDS. Cell. 1986;45(5):637–648. doi: 10.1016/0092-8674(86)90778-62423250
106. Modrow S, Hahn BH, Shaw GM, Gallo RC, Wong-Staal F, Wolf H, Computer-assisted analysis of envelope protein sequences of seven human immunodeficiency virus isolates: prediction of antigenic epitopes in conserved and variable regions. Journal of virology. 1987;61(2):570–578. 2433466
107. Moore PL, Gray ES, Morris L, Specificity of the autologous neutralizing antibody response. Current opinion in HIV and AIDS. 2009;4(5):358. doi: 10.1097/COH.0b013e32832ea7e820048698
108. Sok D, Pauthner M, Briney B, Lee JH, Saye-Francisco KL, Hsueh J, et al. A Prominent Site of Antibody Vulnerability on HIV Envelope Incorporates a Motif Associated with CCR5 Binding and Its Camouflaging Glycans. Immunity. 2016;45(1):31–45. doi: 10.1016/j.immuni.2016.06.02627438765
109. Zwick MB, Labrijn AF, Wang M, Spenlehauer C, Saphire EO, Binley JM, et al. Broadly neutralizing antibodies targeted to the membrane-proximal external region of human immunodeficiency virus type 1 glycoprotein gp41. Journal of virology. 2001;75(22):10892–10905. doi: 10.1128/JVI.75.22.10892-10905.200111602729
110. Blattner C, Lee JH, Sliepen K, Derking R, Falkowska E, de la Peña AT, et al. Structural delineation of a quaternary, cleavage-dependent epitope at the gp41-gp120 interface on intact HIV-1 Env trimers. Immunity. 2014;40(5):669–680. doi: 10.1016/j.immuni.2014.04.00824768348
111. Falkowska E, Le KM, Ramos A, Doores KJ, Lee JH, Blattner C, et al. Broadly neutralizing HIV antibodies define a glycan-dependent epitope on the prefusion conformation of gp41 on cleaved envelope trimers. Immunity. 2014;40(5):657–668. doi: 10.1016/j.immuni.2014.04.00924768347
112. Huang J, Kang BH, Pancera M, Lee JH, Tong T, Feng Y, et al. Broad and potent HIV-1 neutralization by a human antibody that binds the gp41-gp120 interface. Nature. 2014;515(7525):138–142. doi: 10.1038/nature1360125186731
113. Scharf L, Scheid JF, Lee JH, West AP, Chen C, Gao H, et al. Antibody 8ANC195 reveals a site of broad vulnerability on the HIV-1 envelope spike. Cell reports. 2014;7(3):785–795. doi: 10.1016/j.celrep.2014.04.00124767986
114. Kwong PD, Mascola JR, Nabel GJ, Broadly neutralizing antibodies and the search for an HIV-1 vaccine: the end of the beginning. Nature Reviews Immunology. 2013;13(9):693–701. doi: 10.1038/nri351623969737
115. Ramsey DC, Scherrer MP, Zhou T, Wilke CO, The relationship between relative solvent accessibility and evolutionary rate in protein evolution. Genetics. 2011;188:479–488. doi: 10.1534/genetics.111.12802521467571
116. Zhou T, Lynch RM, Chen L, Acharya P, Wu X, Doria-Rose NA, et al. Structural repertoire of HIV-1-neutralizing antibodies targeting the CD4 supersite in 14 donors. Cell. 2015;161(6):1280–1292. doi: 10.1016/j.cell.2015.05.00726004070
117. Zhou T, Georgiev I, Wu X, Yang ZY, Dai K, Finzi A, et al. Structural basis for broad and potent neutralization of HIV-1 by antibody VRC01. Science. 2010;329(5993):811–817. doi: 10.1126/science.119281920616231
118. Klein F, Diskin R, Scheid JF, Gaebler C, Mouquet H, Georgiev IS, et al. Somatic mutations of the immunoglobulin framework are generally required for broad and potent HIV-1 neutralization. Cell. 2013;153(1):126–138. doi: 10.1016/j.cell.2013.03.01823540694
119. Zolla-Pazner S, Cardozo T, Structure–function relationships of HIV-1 envelope sequence-variable regions refocus vaccine design. Nature reviews Immunology. 2010;10(7):527–535. doi: 10.1038/nri280120577269
120. Yusim K, Kesmir C, Gaschen B, Addo MM, Altfeld M, Brunak S, et al. Clustering patterns of cytotoxic T-lymphocyte epitopes in human immunodeficiency virus type 1 (HIV-1) proteins reveal imprints of immune evasion on HIV-1 global variation. Journal of virology. 2002;76(17):8757–8768. doi: 10.1128/JVI.76.17.8757-8768.200212163596
121. Kouyos RD, Leventhal GE, Hinkley T, Haddad M, Whitcomb JM, Petropoulos CJ, et al. Exploring the complexity of the HIV-1 fitness landscape. PLoS Genet. 2012;8(3):e1002551. doi: 10.1371/journal.pgen.100255122412384
122. Lee B, Sharron M, Montaner LJ, Weissman D, Doms RW, Quantification of CD4, CCR5, and CXCR4 levels on lymphocyte subsets, dendritic cells, and differentially conditioned monocyte-derived macrophages. Proceedings of the National Academy of Sciences. 1999;96(9):5215–5220. doi: 10.1073/pnas.96.9.5215
123. Kabat D, Kozak SL, Wehrly K, Chesebro B, Differences in CD4 dependence for infectivity of laboratory-adapted and primary patient isolates of human immunodeficiency virus type 1. Journal of virology. 1994;68(4):2570–2577. 8139036
124. Levy JA, Pathogenesis of human immunodeficiency virus infection. Microbiological reviews. 1993;57(1):183–289. 8464405
125. Berger EA, Murphy PM, Farber JM, Chemokine receptors as HIV-1 coreceptors: roles in viral entry, tropism, and disease. Annual review of immunology. 1999;17(1):657–700. doi: 10.1146/annurev.immunol.17.1.65710358771
126. Ablashi D, Berneman Z, Kramarsky B, Whitman J, Asano Y, Pearson G, Human herpesvirus-7 (HHV-7): current status. Clinical and diagnostic virology. 1995;4(1):1–13. doi: 10.1016/0928-0197(95)00005-S15566823
127. Wei X, Decker JM, Liu H, Zhang Z, Arani RB, Kilby JM, et al. Emergence of resistant human immunodeficiency virus type 1 in patients receiving fusion inhibitor (T-20) monotherapy. Antimicrobial agents and chemotherapy. 2002;46(6):1896–1905. doi: 10.1128/AAC.46.6.1896-1905.200212019106
128. Reed LJ, Muench H, A simple method of estimating fifty per cent endpoints. American journal of epidemiology. 1938;27(3):493–497.
129. Stamatakis A, RAxML version 8: a tool for phylogenetic analysis and post-analysis of large phylogenies. Bioinformatics. 2014; p. btu033.
130. Touw WG, Baakman C, Black J, te Beek TA, Krieger E, Joosten RP, et al. A series of PDB-related databanks for everyday needs. Nucleic acids research. 2014; p. gku1028.
131. Kabsch W, Sander C, Dictionary of protein secondary structure: pattern recognition of hydrogen-bonded and geometrical features. Biopolymers. 1983;22(12):2577–2637. doi: 10.1002/bip.3602212116667333
132. Tien MZ, Meyer AG, Sydykova DK, Spielman SJ, Wilke CO, Maximum allowed solvent accessibilites of residues in proteins. PloS one. 2013;8(11):e80635. doi: 10.1371/journal.pone.008063524278298
133. Pancera M, Zhou T, Druz A, Georgiev IS, Soto C, Gorman J, et al. Structure and immune recognition of trimeric pre-fusion HIV-1 Env. Nature. 2014;514(7523):455–461. doi: 10.1038/nature1380825296255
134. Zhang M, Gaschen B, Blay W, Foley B, Haigwood N, Kuiken C, et al. Tracking global patterns of N-linked glycosylation site variation in highly variable viral glycoproteins: HIV, SIV, and HCV envelopes and influenza hemagglutinin. Glycobiology. 2004;14(12):1229–1246. doi: 10.1093/glycob/cwh10615175256
135. Leonard CK, Spellman MW, Riddle L, Harris RJ, Thomas JN, Gregory T, Assignment of intrachain disulfide bonds and characterization of potential glycosylation sites of the type 1 recombinant human immunodeficiency virus envelope glycoprotein (gp120) expressed in Chinese hamster ovary cells. Journal of Biological Chemistry. 1990;265(18):10373–10382. 2355006