Journal
NATURE COMMUNICATIONS
Volume 12, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41467-021-27075-0
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Funding
- Swiss National Science Foundation (SNF) [314730_152663, 314730_172790]
- European Union's Horizon 2020 research and innovation program [681032]
- Swiss government (through SERI) [15.0337]
- Gilead Cure Grant
- Clinical Priority Research Program of the University of Zurich
- Yvonne-Jacob Foundation
- SNF [324730B_179571, PZ00P3-142411, BSSGI0_155851, 310030_192689, 310030B_166676, 31003A_146278, 33CS30_ 148522]
- SNSF Spark grant [CRSK-3_190705]
- small nested SHCS project [744]
- SHCS research foundation
- Swiss National Science Foundation (SNF) [314730_152663, 310030_192689, CRSK-3_190705, 31003A_146278] Funding Source: Swiss National Science Foundation (SNF)
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The V3-crown of the HIV-1 envelope protein largely elicits non-neutralizing antibodies, but can be targeted by broadly neutralizing designed ankyrin repeat proteins recognizing two conformations, one of which resembles CCR5-bound V3.
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. Challenging this view, we present V3-crown directed broadly neutralizing Designed Ankyrin Repeat Proteins (bnDs) matching the breadth of V3-base bnAbs. While most bnAbs target prefusion Env, V3-crown bnDs bind open Env conformations triggered by CD4 engagement. BnDs achieve breadth by focusing on highly conserved residues that are accessible in two distinct V3 conformations, one of which resembles CCR5-bound V3. We further show 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. Our results indicate a role of V3-crown responses and its conformational preferences in bnAb development to be considered in preventive and therapeutic approaches. The V3-crown of the HIV-1 envelope protein largely elicits non-neutralizing antibodies. Here, the authors show that the V3-crown can be targeted by broadly neutralizing designed ankyrin repeat proteins recognizing two conformations one of which resembles CCR5- bound V3.
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