Distinct conformations of the HIV-1 V3 loop crown are targetable for broad neutralization. Nature Communications
The V3 loop of the HIV-1 envelope (Env) protein elicits a vigorous, but largely non-neutralizing antibody response directed to the V3-crown, whereas rare broadly neutralizing antibodies (bnAbs) target the V3-base.
In this work, Friedrich et al. used the Designed Ankyrin Repeat Proteins (DARPin) technology in order to define conformational states of the V3-crown that are targetable for broad neutralization.
While most bnAbs target prefusion Env, V3-crown bnDs binded open Env conformations triggered by CD4 engagement. BnDs achieved breadth by focusing on highly conserved residues that are accessible in two distinct V3 conformations, one of which resembles CCR5-bound V3.
The authors showed that these V3-crown conformations can, in principle, be attacked by antibodies. Supporting this conclusion, analysis of antibody binding activity in the Swiss 4.5 K HIV-1 cohort (n = 4,281) revealed a co-evolution of V3-crown reactivities and neutralization breadth.
In sum, these findings strongly suggest that directing antibody responses to distinct V3-crown conformations accessible after CD4 attachment should be feasible, thus opening roads for developing vaccine strategies to elicit bnD-like V3-crown bnAbs.
Exploiting this knowledge will likely require the design of appropriate epitope scaffolds to be used as immunogens in order to channel the polyclonal V3-crown response to the desired specificity. These responses will likely not be potent, but due to their high breadth and capacity to recognize an entry state in which bnAbs targeting prefusion Env have less activity, may add important functionality to multivalent vaccines.