HIV-1 neutralization tiers are not relevant for inhibitors targeting the pre-hairpin intermediate

Abstract

HIV-1 strains are categorized into one of three neutralization tiers based on the relative ease by which they are neutralized by plasma from HIV-1 infected donors not on antiretroviral therapy; tier-1 strains are particularly sensitive to neutralization while tier-2 and tier-3 strains are increasingly difficult to neutralize. Most broadly neutralizing antibodies (bnAbs) previously described target the native prefusion conformation of HIV-1 Envelope (Env), but the relevance of the tiered categories for inhibitors targeting another Env conformation, the pre-hairpin intermediate, is not well understood. Here we show that two inhibitors targeting distinct highly-conserved regions of the pre-hairpin intermediate have strikingly consistent neutralization potencies (within ~100-fold for a given inhibitor) against strains in all three neutralization tiers of HIV-1; in contrast, best-in-class bnAbs targeting diverse Env epitopes vary by more than 10,000-fold in potency against these strains. Our results indicate that antisera-based HIV-1 neutralization tiers are not relevant for inhibitors targeting the pre-hairpin intermediate and highlight the potential for therapies and vaccine efforts targeting this conformation.

Structure-guided stabilization improves the ability of the HIV-1 gp41 hydrophobic pocket to elicit neutralizing antibodies

“…S7b-d ), in line with the previous observation that PHI-targeting antibodies have weak but broad neutralization. 20,35…”

“…31 Second, an engineered version of D5 bearing additional amino acid substitutions in the heavy chain CDR loops, D5_AR, was able to neutralize tier 2 and tier 3 viruses. 20,35 Although D5_AR is less potent than other broadly neutralizing antibodies, these results serve as an important proof of concept that antibodies targeting the PHI can broadly neutralize HIV-1 viruses.…”

“…First, the activity of the pocket-targeting D5 antibody can be potentiated >1,000-fold by expression of FcγRI (CD64) on target cells in in vitro neutralization assays, leading to neutralization of tier 2 and tier 3 viruses, which are more representative of circulating strains. 34,35 Since FcγRI is expressed on cells such as macrophages and dendritic cells that are prevalent in mucosal surfaces during the early stages of HIV-1 infection, it has been suggested that this potentiation might be relevant during sexual HIV-1 transmission. 31 Second, an engineered version of D5 bearing additional amino acid substitutions in the heavy chain CDR loops, D5_AR, was able to neutralize tier 2 and tier 3 viruses.…”