Abstract
HIV-1 vaccine design aims to develop an immunogen that elicits broadly neutralizing antibodies against a desired epitope, while eliminating responses to off-target regions of HIV-1 Env. We report characterization of Ab1245, an off-target antibody against the Env gp120-gp41 interface, from V3-glycan patch immunogen-primed and boosted macaques. A 3.7 Å cryo-EM structure of an Ab1245-Env complex reveals one Ab1245 Fab binding asymmetrically to Env trimer at the gp120-gp41 interface using its long CDRH3 to mimic regions of gp41. The mimicry includes positioning of a CDRH3 methionine into the gp41 tryptophan clasp, resulting in displacement of the fusion peptide and fusion peptide-proximal region. Despite fusion peptide displacement, Ab1245 is non-neutralizing even at high concentrations, raising the possibility that only two fusion peptides per trimer are required for viral–host membrane fusion. These structural analyses facilitate immunogen design to prevent elicitation of Ab1245-like antibodies that block neutralizing antibodies against the fusion peptide.
Highlights
Recent efforts in vaccine design for the HIV-1 virus have focused on developing neutralizing adaptive immune responses to the HIV-1 Env glycoprotein via sequential immunization[1,2,3]
We showed that RC1 and/or RC1-4fill that had been multimerized on virus-like particles (VLPs) elicited antibodies that recognized the V3-glycan patch in wild-type mice, rabbits, and non-human primates (NHPs)[4]
Four NHPs primed with RC1-4fill-VLPs4 were boosted sequentially with (i) VLPS coupled with 11MUTB-4fill[16], (ii) VLPs
Summary
Recent efforts in vaccine design for the HIV-1 virus have focused on developing neutralizing adaptive immune responses to the HIV-1 Env glycoprotein via sequential immunization[1,2,3]. Studies of broadly neutralizing antibodies (bNAbs) isolated from HIV + human donors have informed immunogen design efforts for various epitopes on the Env trimer, including the V3-glycan patch[4,5], the fusion peptide (FP)[6,7], and the CD4-binding site[8,9]. EM structure of a BG505 Env trimer bound to a monoclonal antibody (Ab1245) isolated from a rhesus macaque after a sequential immunization protocol that included multimerized
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
