Difficult-to-neutralize global HIV-1 isolates are neutralized by antibodies targeting open envelope conformations

Abstract

The HIV-1 envelope (Env) is the target for neutralizing antibodies and exists on the surface of virions in open or closed conformations. Difficult-to-neutralize viruses (tier 2) express Env in a closed conformation antigenic for broadly neutralizing antibodies (bnAbs) but not for third variable region (V3) antibodies. Here we show that select V3 macaque antibodies elicited by Env vaccination can neutralize 26% of otherwise tier 2 HIV-1 isolates in standardized virus panels. The V3 antibodies only bound to Env in its open conformation. Thus, Envs on tier 2 viruses sample a state where the V3 loop is not in its closed conformation position. Envelope second variable region length, glycosylation sites and V3 amino acids were signatures of neutralization sensitivity. This study determined that open conformations of Env with V3 exposed are present on a subset of otherwise neutralization-resistant virions, therefore neutralization of tier 2 HIV-1 does not always indicate bnAb induction.

Structural basis of transmembrane coupling of the HIV-1 envelope glycoprotein

“…10). Although virus neutralization is not a direct measure of antibody binding to the Env as the process could be influenced by other factors such as possible CT-matrix protein (MA) interaction and membrane fusion kinetics, earlier studies have shown that loss of neutralization is overall correlated with the loss of Env binding to bnAbs 5,37 . We generated 28 Env mutants using the sequence of a TMD-KS and CT LLP2 (C789) are expressed separately: TMD-KS is isotopically-enriched for NMR readout while CT LLP2 carries the spin-label (at C789).…”

Recapitulation of HIV-1 Env-Antibody Coevolution in Macaques Leading to Neutralization Breadth

“…This is in addition to 10% heat-inactivated fetal bovine serum in the complete RPMI1640 culture medium. Target viruses express HIV-1 Envs reported elsewhere (29,30,86).…”

“…DH650 bound to the gp120 core was deposited with database code PDB ID xxxx. (29,30,86) are depicted. (B) Neutralization curves for longitudinal plasma specimens and purified plasma IgG (highlighted bold) from RM5695 show the development of broad neutralization.…”

Signal Peptide of HIV-1 Envelope Modulates Glycosylation Impacting Exposure of V1V2 Epitopes

“…trimers toward more open conformations(71)(72)(73). Altogether, these data indicate that SP swapping subtly modifies the proportion of Env oligosaccharide content and the antigenicity of V1V2 without triggering global structural transformations on Env.As indicated by comparable Env incorporation and virus infectivity, SP exchanges had no deleterious effects on Env functions.…”