Escolano, A. | Search bioRxiv

bioRxiv2021

Antibody elicited by HIV-1 immunogen vaccination in macaques displaces Env fusion peptide and destroys a neutralizing epitope

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. Here we report isolation and 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, implying 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.

immunology↗

bioRxiv2020

A Broadly Neutralizing Macaque Monoclonal Antibody Against the HIV-1 V3-Glycan Patch

A small fraction of HIV-1 infected humans develop potent broadly neutralizing antibodies (bNAbs) against HIV-1 that can protect macaques from infection with simian immunodeficiency HIV chimeric virus (SHIV). Similarly, a small number of macaques infected with SHIVs also develop broadly neutralizing serologic activity, but less is known about the nature of these simian antibodies. Here we report on a monoclonal antibody, Ab1485, isolated from a macaque infected with SHIVAD8 that developed broadly neutralizing serologic activity mapping to the V3-glycan region of HIV-1 Env. Ab1485 neutralizes 38.1 % of HIV-1 isolates in a panel of 42 pseudoviruses with a geometric mean IC50 of 0.055 g/ml and SHIVAD8 with an IC50 of 0.028 g/ml. Ab1485 binds to the V3-glycan epitope in a glycan-dependent manner as determined by ELISA and neutralization assays with JRCSF mutant viruses. A 3.5 [A] cryo-electron microscopy structure of Ab1485 in complex with a native-like SOSIP Env trimer showed conserved contacts with the N332gp120 glycan and gp120 GDIR peptide motif, but in a distinct Env-binding orientation relative to human V3/N332gp120 glycan-targeting bNAbs. Finally, intravenous infusion of Ab1485 protected macaques from a high dose intrarectal challenge with SHIVAD8. We conclude that macaques can develop bNAbs against the V3-glycan patch that resemble human V3-glycan bNAbs. Significance statementRhesus macaques infected with SHIV are an important model for evaluating HIV-1 prevention and therapy strategies and can also be used to evaluate humoral immune responses to candidate HIV-1 vaccines, but whether macaques produce human-like bNAbs has not been evaluated. Like HIV-1 infected humans, 10-20% of the SHIVAD8 challenged macaques develop low levels of neutralizing antibodies, and only one macaque has developed broad and potent serologic neutralizing activity. We have examined the antibody response of this macaque (CE8J) and we report on the cloning and molecular characterization of a bNAb produced in this elite neutralizing non-human primate, its structure bound to an HIV-1 Env trimer, and the implications for development of vaccines targeting the V3-glycan patch of Env.

immunology↗