title: Antibodies VRC01 and 10E8 neutralize HIV-1 with high breadth and potency even with Ig-framework regions substantially reverted to germline.
abstract: Abs capable of effectively neutralizing HIV-1 generally exhibit very high levels of somatic hypermutation, both in their CDR and framework-variable regions. In many cases, full reversion of the Ab-framework mutations back to germline results in substantial to complete loss of HIV-1-neutralizing activity. However, it has been unclear whether all or most of the observed framework mutations would be necessary or whether a small subset of these mutations might be sufficient for broad and potent neutralization. To address this issue and to explore the dependence of neutralization activity on the level of somatic hypermutation in the Ab framework, we applied a computationally guided framework-reversion procedure to two broadly neutralizing anti-HIV-1 Abs, VRC01 and 10E8, which target two different HIV-1 sites of vulnerability. Ab variants in which up to 78% (38 of 49 for VRC01) and 89% (31 of 35 for 10E8) of framework mutations were reverted to germline retained breadth and potency within 3-fold of the mature Abs when evaluated on a panel of 21 diverse viral strains. Further, a VRC01 variant with an ∼50% framework-reverted L chain showed a 2-fold improvement in potency over the mature Ab. Our results indicate that only a small number of Ab-framework mutations may be sufficient for high breadth and potency of HIV-1 neutralization by Abs VRC01 and 10E8. Partial framework revertants of HIV-1 broadly neutralizing Abs may present advantages over their highly mutated counterparts as Ab therapeutics and as targets for immunogen design.
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Ivelin S
authors.initials: IS
authors.lastname: Georgiev
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Rudicell
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Kevin O
authors.initials: KO
authors.lastname: Saunders
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Shi
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Tatsiana
authors.initials: T
authors.lastname: Kirys
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Krisha
authors.initials: K
authors.lastname: McKee
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Sijy
authors.initials: S
authors.lastname: O'Dell
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Gwo-Yu
authors.initials: GY
authors.lastname: Chuang
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Zhi-Yong
authors.initials: ZY
authors.lastname: Yang
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Gilad
authors.initials: G
authors.lastname: Ofek
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Connors
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Mascola
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Nabel
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Kwong
mesh_terms: D000595:Amino Acid Sequence; D005803:Genes, Immunoglobulin; D018095:Germ-Line Mutation; D015483:HIV Antibodies / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007147:Immunoglobulin Light Chains / Q000235:genetics; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009500:Neutralization Tests; D011487:Protein Conformation; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D027041:Somatic Hypermutation, Immunoglobulin
chemical_list: D015483:HIV Antibodies; D007143:Immunoglobulin Heavy Chains; D007147:Immunoglobulin Light Chains