A New Glycan-Dependent CD4-Binding Site Neutralizing Antibody Exerts Pressure on HIV-1 In Vivo.

TitleA New Glycan-Dependent CD4-Binding Site Neutralizing Antibody Exerts Pressure on HIV-1 In Vivo.
Publication TypeJournal Article
Year of Publication2015
AuthorsFreund NT, Horwitz JA, Nogueira L, Sievers SA, Scharf L, Scheid JF, Gazumyan A, Liu C, Velinzon K, Goldenthal A, Sanders RW, Moore JP, Bjorkman PJ, Seaman MS, Walker BD, Klein F, Nussenzweig MC
JournalPLoS Pathog
Date Published10/30/2015

The CD4 binding site (CD4bs) on the envelope glycoprotein is a major site of vulnerability that is conserved among different HIV-1 isolates. Many broadly neutralizing antibodies (bNAbs) to the CD4bs belong to the VRC01 class, sharing highly restricted origins, recognition mechanisms and viral escape pathways. We sought to isolate new anti-CD4bs bNAbs with different origins and mechanisms of action. Using a gp120 2CC core as bait, we isolated antibodies encoded by IGVH3-21 and IGVL3-1 genes with long CDRH3s that depend on the presence of the N-linked glycan at position-276 for activity. This binding mode is similar to the previously identified antibody HJ16, however the new antibodies identified herein are more potent and broad. The most potent variant, 179NC75, had a geometric mean IC80 value of 0.42 μg/ml against 120 Tier-2 HIV-1 pseudoviruses in the TZM.bl assay. Although this group of CD4bs glycan-dependent antibodies can be broadly and potently neutralizing in vitro, their in vivo activity has not been tested to date. Here, we report that 179NC75 is highly active when administered to HIV-1-infected humanized mice, where it selects for escape variants that lack a glycan site at position-276. The same glycan was absent from the virus isolated from the 179NC75 donor, implying that the antibody also exerts selection pressure in humans.

Alternate JournalPLoS Pathog.
PubMed ID26516768
PubMed Central IDPMC4627763
Grant List1 P01 AI100148 / AI / NIAID NIH HHS / United States
P01 AI110657 / AI / NIAID NIH HHS / United States
R01 AI078799 / AI / NIAID NIH HHS / United States
UM1 AI100663 / AI / NIAID NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
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