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

Abstract

AbstractA 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 μg/ml and SHIVAD8 with an IC50 of 0.028 μg/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 Å 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.