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Publication Abstract from PubMed

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 A 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.

Antibody elicited by HIV-1 immunogen vaccination in macaques displaces Env fusion peptide and destroys a neutralizing epitope.,Abernathy ME, Gristick HB, Vielmetter J, Keeffe JR, Gnanapragasam PNP, Lee YE, Escolano A, Gautam R, Seaman MS, Martin MA, Nussenzweig MC, Bjorkman PJ NPJ Vaccines. 2021 Oct 25;6(1):126. doi: 10.1038/s41541-021-00387-4. PMID:34697307^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.