Prediction of VRC01 neutralization sensitivity by HIV-1 gp160 sequence features.
Amino Acid Sequence
Antibodies, Monoclonal
/ genetics
Antibodies, Neutralizing
/ immunology
Binding Sites
Broadly Neutralizing Antibodies
CD4 Antigens
Computer Simulation
Forecasting
/ methods
Glycosylation
HIV Antibodies
/ immunology
HIV Envelope Protein gp160
/ genetics
HIV Infections
/ virology
HIV-1
/ immunology
Humans
Protein Binding
Journal
PLoS computational biology
ISSN: 1553-7358
Titre abrégé: PLoS Comput Biol
Pays: United States
ID NLM: 101238922
Informations de publication
Date de publication:
04 2019
04 2019
Historique:
received:
24
05
2018
accepted:
14
03
2019
revised:
11
04
2019
pubmed:
2
4
2019
medline:
22
5
2019
entrez:
2
4
2019
Statut:
epublish
Résumé
The broadly neutralizing antibody (bnAb) VRC01 is being evaluated for its efficacy to prevent HIV-1 infection in the Antibody Mediated Prevention (AMP) trials. A secondary objective of AMP utilizes sieve analysis to investigate how VRC01 prevention efficacy (PE) varies with HIV-1 envelope (Env) amino acid (AA) sequence features. An exhaustive analysis that tests how PE depends on every AA feature with sufficient variation would have low statistical power. To design an adequately powered primary sieve analysis for AMP, we modeled VRC01 neutralization as a function of Env AA sequence features of 611 HIV-1 gp160 pseudoviruses from the CATNAP database, with objectives: (1) to develop models that best predict the neutralization readouts; and (2) to rank AA features by their predictive importance with classification and regression methods. The dataset was split in half, and machine learning algorithms were applied to each half, each analyzed separately using cross-validation and hold-out validation. We selected Super Learner, a nonparametric ensemble-based cross-validated learning method, for advancement to the primary sieve analysis. This method predicted the dichotomous resistance outcome of whether the IC50 neutralization titer of VRC01 for a given Env pseudovirus is right-censored (indicating resistance) with an average validated AUC of 0.868 across the two hold-out datasets. Quantitative log IC50 was predicted with an average validated R2 of 0.355. Features predicting neutralization sensitivity or resistance included 26 surface-accessible residues in the VRC01 and CD4 binding footprints, the length of gp120, the length of Env, the number of cysteines in gp120, the number of cysteines in Env, and 4 potential N-linked glycosylation sites; the top features will be advanced to the primary sieve analysis. This modeling framework may also inform the study of VRC01 in the treatment of HIV-infected persons.
Identifiants
pubmed: 30933973
doi: 10.1371/journal.pcbi.1006952
pii: PCOMPBIOL-D-18-00849
pmc: PMC6459550
doi:
Substances chimiques
Antibodies, Monoclonal
0
Antibodies, Neutralizing
0
Broadly Neutralizing Antibodies
0
CD4 Antigens
0
HIV Antibodies
0
HIV Envelope Protein gp160
0
VRC01 monoclonal antibody
0
gp160 protein, Human immunodeficiency virus 1
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1006952Subventions
Organisme : NIAID NIH HHS
ID : F31 AI140836
Pays : United States
Organisme : NIAID NIH HHS
ID : UM1 AI068614
Pays : United States
Organisme : NIAID NIH HHS
ID : R37 AI054165
Pays : United States
Organisme : NIAID NIH HHS
ID : UM1 AI068635
Pays : United States
Organisme : NIH HHS
ID : S10 OD020069
Pays : United States
Organisme : NIAID NIH HHS
ID : UM1 AI069436
Pays : United States
Organisme : NIAID NIH HHS
ID : U01 AI069436
Pays : United States
Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
Références
J Virol. 1993 Nov;67(11):6897-902
pubmed: 8411395
AIDS Res Hum Retroviruses. 2005 Dec;21(12):1016-30
pubmed: 16379605
J Acquir Immune Defic Syndr. 2015 May 1;69(1):109-18
pubmed: 25942462
J Virol. 2011 Sep;85(17):8954-67
pubmed: 21715490
Nature. 2013 Nov 14;503(7475):224-8
pubmed: 24172905
Cell. 2016 May 5;165(4):813-26
pubmed: 27114034
J Biol Chem. 2012 Dec 14;287(51):43170-9
pubmed: 23100255
PLoS One. 2012;7(5):e37157
pubmed: 22606344
N Engl J Med. 2015 Nov 19;373(21):2025-2037
pubmed: 26488565
J Theor Biol. 1986 Mar 21;119(2):205-18
pubmed: 3461222
J Virol. 2013 Sep;87(18):10047-58
pubmed: 23843642
Nucleic Acids Res. 2015 Jul 1;43(W1):W213-9
pubmed: 26044712
Virology. 2017 May;505:193-209
pubmed: 28279830
Virology. 1993 Sep;196(1):332-7
pubmed: 8356803
Stat Commun Infect Dis. 2017 Jan;9(1):
pubmed: 29218117
Clin Exp Immunol. 2015 Dec;182(3):289-301
pubmed: 26332605
Biochem Soc Symp. 1974;(40):17-26
pubmed: 4620382
BMC Bioinformatics. 2014 Mar 19;15:77
pubmed: 24646213
Curr Opin HIV AIDS. 2015 May;10(3):135-43
pubmed: 25760932
Lancet Respir Med. 2015 Jan;3(1):42-52
pubmed: 25466337
J R Stat Soc Ser C Appl Stat. 2015 Jan 1;64(1):49-73
pubmed: 25641990
J Virol. 2016 Dec 16;91(1):
pubmed: 27795431
Proc Natl Acad Sci U S A. 2012 Jul 24;109(30):E2083-90
pubmed: 22745174
Biometrics. 2008 Mar;64(1):198-207
pubmed: 17608781
J Virol. 2015 Dec 30;90(6):2884-94
pubmed: 26719247
Vaccine. 2016 Nov 11;34(47):5792-5801
pubmed: 27756485
Annu Rev Immunol. 2016 May 20;34:635-59
pubmed: 27168247
Stat Appl Genet Mol Biol. 2007;6:Article25
pubmed: 17910531
Curr HIV/AIDS Rep. 2016 Feb;13(1):31-7
pubmed: 26841901
PLoS Comput Biol. 2018 Apr 20;14(4):e1006093
pubmed: 29677181
Nature. 2011 Nov 23;480(7377):336-43
pubmed: 22113616
J Virol. 2009 Aug;83(15):7728-38
pubmed: 19474108
Immunity. 2016 Nov 15;45(5):1108-1121
pubmed: 27851912
J Virol. 1994 Feb;68(2):674-80
pubmed: 7507184
Virology. 2012 Oct 25;432(2):505-10
pubmed: 22832125
PLoS Comput Biol. 2015 Feb 03;11(2):e1003973
pubmed: 25646817
N Engl J Med. 2016 Nov 24;375(21):2019-2021
pubmed: 27959740
N Engl J Med. 2016 Nov 24;375(21):2037-2050
pubmed: 27959728
Biometrics. 2021 Mar;77(1):9-22
pubmed: 33043428
J Virol. 2011 Jul;85(14):7029-36
pubmed: 21543485
J Virol. 2012 Oct;86(19):10857-61
pubmed: 22837204
EBioMedicine. 2016 Oct;12:196-207
pubmed: 27612593
Sci Transl Med. 2015 Dec 23;7(319):319ra206
pubmed: 26702094
PLoS Med. 2017 Nov 14;14(11):e1002435
pubmed: 29136037
J Clin Epidemiol. 2001 Jan;54(1):68-85
pubmed: 11165470
PLoS Comput Biol. 2017 Oct 24;13(10):e1005789
pubmed: 29065122
Nature. 2013 Nov 14;503(7475):277-80
pubmed: 24172896
Nucleic Acids Res. 2014 Jul;42(Web Server issue):W64-71
pubmed: 24782517
Biotechniques. 2010 May;48(5):405-8
pubmed: 20569214
Nature. 2012 Oct 18;490(7420):417-20
pubmed: 22960785
PLoS Med. 2008 Jan 3;5(1):e9
pubmed: 18177204
Nucleic Acids Res. 2011 Jan;39(Database issue):D411-9
pubmed: 21071423
Biopolymers. 1983 Dec;22(12):2577-637
pubmed: 6667333
PLoS One. 2013 Dec 02;8(12):e80562
pubmed: 24312481
J Virol. 2000 May;74(9):4183-91
pubmed: 10756031
J Virol. 1990 Jul;64(7):3240-8
pubmed: 2352323
Proc Natl Acad Sci U S A. 2013 Jun 25;110(26):10598-603
pubmed: 23754383
Science. 2013 Sep 13;341(6151):1199-204
pubmed: 24031012
J Virol. 2015 Apr;89(8):4201-13
pubmed: 25631091
J Virol. 2012 Nov;86(22):12105-14
pubmed: 22933284
J Infect Dis. 2010 Aug 15;202(4):595-605
pubmed: 20608874
PLoS Pathog. 2013 Oct;9(10):e1003738
pubmed: 24204277
Immunity. 2013 Aug 22;39(2):245-58
pubmed: 23911655
Biometrics. 2013 Jun;69(2):328-37
pubmed: 23421613
J Biol Chem. 2011 Apr 22;286(16):14531-41
pubmed: 21325278
Retrovirology. 2014 Apr 23;11:32
pubmed: 24758333
Nat Med. 2011 Mar;17(3):366-71
pubmed: 21358627
Science. 2010 Aug 13;329(5993):811-7
pubmed: 20616231
Electron J Stat. 2015;9(1):1583-1607
pubmed: 26279737
Nature. 2011 Sep 22;477(7365):466-70
pubmed: 21849977
PLoS One. 2017 Nov 17;12(11):e0185959
pubmed: 29149197
PLoS Pathog. 2015 May 29;11(5):e1004932
pubmed: 26023780
J Immunol Methods. 2012 Jan 31;375(1-2):57-67
pubmed: 21968254
PLoS Comput Biol. 2010 Oct 07;6(10):e1000955
pubmed: 20949103
Science. 2010 Aug 13;329(5993):856-61
pubmed: 20616233
Proc Natl Acad Sci U S A. 2018 Sep 4;115(36):E8378-E8387
pubmed: 30127007
Nat Commun. 2015 Sep 29;6:8443
pubmed: 26416571
Nature. 2012 Dec 6;492(7427):118-22
pubmed: 23103874
PLoS Pathog. 2016 Jul 19;12(7):e1005742
pubmed: 27434311