title: CD4-Induced Antibodies Promote Association of the HIV-1 Envelope Glycoprotein with CD4-Binding Site Antibodies.
abstract: The HIV-1 envelope glycoprotein (Env) is a trimer of gp120/gp41 heterodimers that mediates viral entry. Env binds cellular CD4, an association which stabilizes a conformation favorable to its subsequent association with a coreceptor, typically CCR5 or CXCR4. The CD4- and coreceptor-binding sites serve as epitopes for two classes of HIV-1-neutralizing antibodies: CD4-binding site (CD4bs) and CD4-induced (CD4i) antibodies, respectively. Here we observed that, at a fixed total concentration, mixtures of the CD4i antibodies (E51 or 412d) and the CD4bs antibody VRC01 neutralized the HIV-1 isolates 89.6, ADA, SG3, and SA32 more efficiently than either antibody alone. We found that E51, and to a lesser extent 412d and 17b, promoted association of four CD4bs antibodies to the Env trimer but not to monomeric gp120. We further demonstrated that the binding of the sulfotyrosine-binding pocket by CCR5mim2-Ig was sufficient for promoting CD4bs antibody binding to Env. Interestingly, the relationship is not reciprocal: CD4bs antibodies were not as efficient as CD4-Ig at promoting E51 or 412d binding to Env trimer. Consistent with these observations, CD4-Ig, but none of the CD4bs antibodies tested, substantially increased HIV-1 infection of a CD4-negative, CCR5-positive cell line. We conclude that the ability of CD4i antibodies to promote VRC01 association with Env trimers accounts for the increase potency of VRC01 and CD4i antibody mixtures. Our data further suggest that potent CD4bs antibodies avoid inducing Env conformations that bind CD4i antibodies or CCR5.
  
  
  
  Potent HIV-1-neutralizing antibodies can prevent viral transmission and suppress an ongoing infection. Here we show that CD4-induced (CD4i) antibodies, which recognize the conserved coreceptor-binding site of the HIV-1 envelope glycoprotein (Env), can increase the association of Env with potent broadly neutralizing antibodies that recognize the CD4-binding site (CD4bs antibodies). We further show that, unlike soluble forms of CD4, CD4bs antibodies poorly induce envelope glycoprotein conformations that efficiently bind CCR5. This study provides insight into the properties of potent CD4bs antibodies and suggests that, under some conditions, CD4i antibodies can improve their potency. These observations may be helpful to the development of vaccines designed to elicit specific antibody classes.
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, Jupiter, Florida, USA mgardner@scripps.edu.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Gardner
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, Jupiter, Florida, USA.
authors.forename: Christoph H
authors.initials: CH
authors.lastname: Fellinger
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, Jupiter, Florida, USA.
authors.forename: Neha R
authors.initials: NR
authors.lastname: Prasad
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, Jupiter, Florida, USA.
authors.forename: Amber S
authors.initials: AS
authors.lastname: Zhou
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, Jupiter, Florida, USA.
authors.forename: Hema R
authors.initials: HR
authors.lastname: Kondur
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, Jupiter, Florida, USA.
authors.forename: Vinita R
authors.initials: VR
authors.lastname: Joshi
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, Jupiter, Florida, USA.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Quinlan
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, Jupiter, Florida, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Farzan
mesh_terms: D057134:Antibodies, Neutralizing / Q000276:immunology*; D001665:Binding Sites; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002460:Cell Line; D015483:HIV Antibodies / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology* / Q000502:physiology; D006801:Humans; D011485:Protein Binding; D053585:Virus Attachment; D054299:env Gene Products, Human Immunodeficiency Virus / Q000276:immunology*
chemical_list: D057134:Antibodies, Neutralizing; D015483:HIV Antibodies; D054299:env Gene Products, Human Immunodeficiency Virus