title: PGV04, an HIV-1 gp120 CD4 binding site antibody, is broad and potent in neutralization but does not induce conformational changes characteristic of CD4.
abstract: Recently, several broadly neutralizing monoclonal antibodies (bnMAbs) directed to the CD4-binding site (CD4bs) of gp120 have been isolated from HIV-1-positive donors. These include VRC01, 3BNC117, and NIH45-46, all of which are capable of neutralizing about 90% of circulating HIV-1 isolates and all of which induce conformational changes in the HIV-1 gp120 monomer similar to those induced by the CD4 receptor. In this study, we characterize PGV04 (also known as VRC-PG04), a MAb with potency and breadth that rivals those of the prototypic VRC01 and 3BNC117. When screened on a large panel of viruses, the neutralizing profile of PGV04 was distinct from those of CD4, b12, and VRC01. Furthermore, the ability of PGV04 to neutralize pseudovirus containing single alanine substitutions exhibited a pattern distinct from those of the other CD4bs MAbs. In particular, substitutions D279A, I420A, and I423A were found to abrogate PGV04 neutralization. In contrast to VRC01, PGV04 did not enhance the binding of 17b or X5 to their epitopes (the CD4-induced [CD4i] site) in the coreceptor region on the gp120 monomer. Furthermore, in contrast to CD4, none of the anti-CD4bs MAbs induced the expression of the 17b epitope on cell surface-expressed cleaved Env trimers. We conclude that potent CD4bs bnMAbs can display differences in the way they recognize and access the CD4bs and that mimicry of CD4, as assessed by inducing conformational changes in monomeric gp120 that lead to enhanced exposure of the CD4i site, is not uniquely correlated with effective neutralization at the site of CD4 binding on HIV-1.
authors.affiliation: Department of Immunology and Microbial Science and IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Emilia
authors.initials: E
authors.lastname: Falkowska
authors.forename: Alejandra
authors.initials: A
authors.lastname: Ramos
authors.forename: Yu
authors.initials: Y
authors.lastname: Feng
authors.forename: Tongqing
authors.initials: T
authors.lastname: Zhou
authors.forename: Stephanie
authors.initials: S
authors.lastname: Moquin
authors.forename: Laura M
authors.initials: LM
authors.lastname: Walker
authors.forename: Xueling
authors.initials: X
authors.lastname: Wu
authors.forename: Michael S
authors.initials: MS
authors.lastname: Seaman
authors.forename: Terri
authors.initials: T
authors.lastname: Wrin
authors.forename: Peter D
authors.initials: PD
authors.lastname: Kwong
authors.forename: Richard T
authors.initials: RT
authors.lastname: Wyatt
authors.forename: John R
authors.initials: JR
authors.lastname: Mascola
authors.forename: Pascal
authors.initials: P
authors.lastname: Poignard
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Burton
mesh_terms: D019943:Amino Acid Substitution; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000378:metabolism; D057134:Antibodies, Neutralizing / Q000276:immunology* / Q000378:metabolism; D000918:Antibody Specificity / Q000276:immunology; D001666:Binding Sites, Antibody; D015704:CD4 Antigens / Q000737:chemistry* / Q000378:metabolism; D006031:Glycosylation; D015699:HIV Envelope Protein gp120 / Q000737:chemistry* / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D009500:Neutralization Tests; D011485:Protein Binding; D011487:Protein Conformation; D055503:Protein Multimerization
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; D008562:Membrane Glycoproteins