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Cross-reactive HIV-1-neutralizing human monoclonal antibodies identified from a patient with 2F5-like antibodies
Zhongyu Zhu1; Haiyan Rebekah Qin1; Weizao Chen1; Qi Zhao1; Xiaoying Shen2; Robert Schutte2; Yanping Wang1,3; Gilad Ofek4; Emily Streaker1,3; Ponraj Prabakaran1; Genevieve G. Fouda2; Hua-Xin Liao2; John Owens1; Mark Louder4; Yongping Yang4; Kristina-Ana Klaric5; M. Anthony Moody2; John R. Mascola4; Jamie K. Scott5; Peter D. Kwong4; David Montefiori2; Barton F. Haynes2; Georgia D. Tomaras2; Dimiter S. Dimitrov1
2011
Source PublicationJOURNAL OF VIROLOGY
ISSN0022-538X
Volume85Issue:21Pages:11401-11408
Abstract

The genes encoding broadly HIV-1-neutralizing human monoclonal antibodies (MAbs) are highly divergent from their germ line counterparts. We have hypothesized that such high levels of somatic hypermutation could pose a challenge for elicitation of the broadly neutralizing (bn) Abs and that identification of less somatically mutated bn Abs may help in the design of effective vaccine immunogens. In a quest for such bn Abs, phage-and yeast-displayed antibody libraries, constructed using peripheral blood mononuclear cells (PBMCs) from a patient with bn serum containing Abs targeting the epitope of the bn MAb 2F5, were panned against peptides containing the 2F5 epitope and against the HIV-1 gp140(JR-FL). Two MAbs (m66 and m66.6) were identified; the more mutated variant (m66.6) exhibited higher HIV-1-neutralizing activity than m66, although it was weaker than 2F5 in a TZM-bl cell assay. Binding of both MAbs to gp41 alanine substitution mutant peptides required the DKW664-666 core of the 2F5 epitope and two additional upstream residues (L-660,L-663). The MAbs have long (21-residue) heavy-chain third complementarity-determining regions (CDR-H3s), and m66.6 (but not m66) exhibited polyspecific reactivity to self- and non-self-antigens. Both m66 and m66.6 are significantly less divergent from their germ line Ab counterparts than 2F5-they have a total of 11 and 18 amino acid changes, respectively, from the closest VH and V kappa germ line gene products compared to 25 for 2F5. These new MAbs could help explore the complex maturation pathways involved in broad neutralization and its relationship with auto- and polyreactivity and may aid design of vaccine immunogens and development of therapeutics against HIV-1 infection.

DOIhttps://doi.org/10.1128/JVI.05312-11
Indexed BySCI
Language英语
WOS Research AreaVirology
WOS SubjectVirology
WOS IDWOS:000296254400046
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Cited Times [WOS]:63   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionFaculty of Health Sciences
Corresponding AuthorDimiter S. Dimitrov
Affiliation1.National Cancer Institute, Frederick, Maryland
2.Human Vaccine Institute, Durham, North Carolina
3.SAIC, Frederick, Maryland
4.Vaccine Research Center, Bethesda, Maryland
5.Department of Molecular Biology and Biochemistry and Faculty of Health Sciences, Simon Fraser University, Burnaby, British Columbia, Canada
Recommended Citation
GB/T 7714
Zhongyu Zhu,Haiyan Rebekah Qin,Weizao Chen,et al. Cross-reactive HIV-1-neutralizing human monoclonal antibodies identified from a patient with 2F5-like antibodies[J]. JOURNAL OF VIROLOGY,2011,85(21):11401-11408.
APA Zhongyu Zhu.,Haiyan Rebekah Qin.,Weizao Chen.,Qi Zhao.,Xiaoying Shen.,...&Dimiter S. Dimitrov.(2011).Cross-reactive HIV-1-neutralizing human monoclonal antibodies identified from a patient with 2F5-like antibodies.JOURNAL OF VIROLOGY,85(21),11401-11408.
MLA Zhongyu Zhu,et al."Cross-reactive HIV-1-neutralizing human monoclonal antibodies identified from a patient with 2F5-like antibodies".JOURNAL OF VIROLOGY 85.21(2011):11401-11408.
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