Cross-reactive HIV-1-neutralizing human monoclonal antibodies identified from a patient with 2F5-like antibodies.

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TitleCross-reactive HIV-1-neutralizing human monoclonal antibodies identified from a patient with 2F5-like antibodies.
Publication TypeJournal Article
Year of Publication2011
AuthorsZhu, Z, Qin, HRebekah, Chen, W, Zhao, Q, Shen, X, Schutte, R, Wang, Y, Ofek, GA, Streaker, E, Prabakaran, P, Fouda, GG, Liao, H-X, Owens, J, Louder, M, Yang, Y, Klaric, K-A, M Moody, A, Mascola, JR, Scott, JK, Kwong, PD, Montefiori, D, Haynes, BF, Tomaras, GD, Dimitrov, DS
JournalJ Virol
Volume85
Issue21
Pagination11401-8
Date Published2011 Nov
ISSN1098-5514
KeywordsAntibodies, Monoclonal, Antibodies, Neutralizing, Cross Reactions, Epitopes, HIV Antibodies, HIV Infections, HIV-1, Humans, Molecular Sequence Data, Sequence Analysis, DNA
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 DKW(664-666) core of the 2F5 epitope and two additional upstream residues (L(660,663)). 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 Vκ 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.

DOI10.1128/JVI.05312-11
Alternate JournalJ. Virol.
PubMed ID21880764
PubMed Central IDPMC3194990
Grant ListN01-CO-12400 / CO / NCI NIH HHS / United States
U19 AI067854 / AI / NIAID NIH HHS / United States
/ / Intramural NIH HHS / United States