title: Cross-reactive HIV-1-neutralizing human monoclonal antibodies identified from a patient with 2F5-like antibodies.
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.
authors: National Cancer Institute, Frederick, Maryland 21702-1201, USA.
authors: Zhongyu
authors: Z
authors: Zhu
authors: Haiyan Rebekah
authors: HR
authors: Qin
authors: Weizao
authors: W
authors: Chen
authors: Qi
authors: Q
authors: Zhao
authors: Xiaoying
authors: X
authors: Shen
authors: Robert
authors: R
authors: Schutte
authors: Yanping
authors: Y
authors: Wang
authors: Gilad
authors: G
authors: Ofek
authors: Emily
authors: E
authors: Streaker
authors: Ponraj
authors: P
authors: Prabakaran
authors: Genevieve G
authors: GG
authors: Fouda
authors: Hua-Xin
authors: HX
authors: Liao
authors: John
authors: J
authors: Owens
authors: Mark
authors: M
authors: Louder
authors: Yongping
authors: Y
authors: Yang
authors: Kristina-Ana
authors: KA
authors: Klaric
authors: M Anthony
authors: MA
authors: Moody
authors: John R
authors: JR
authors: Mascola
authors: Jamie K
authors: JK
authors: Scott
authors: Peter D
authors: PD
authors: Kwong
authors: David
authors: D
authors: Montefiori
authors: Barton F
authors: BF
authors: Haynes
authors: Georgia D
authors: GD
authors: Tomaras
authors: Dimiter S
authors: DS
authors: Dimitrov
mesh_terms: D000911:Antibodies, Monoclonal / Q000235:genetics / Q000276:immunology*; D057134:Antibodies, Neutralizing / Q000235:genetics / Q000276:immunology*; D003429:Cross Reactions; D000939:Epitopes / Q000235:genetics / Q000276:immunology; D015483:HIV Antibodies / Q000235:genetics / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology* / Q000821:virology; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D008969:Molecular Sequence Data; D017422:Sequence Analysis, DNA
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000939:Epitopes; D015483:HIV Antibodies