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• W3027156749 abstract "Purpose: Broadly HIV-1 neutralizing antibodies (bNAbs) can suppress viremiain humans and represent a novel approach for effective immunotherapy.However, bNAb monotherapy selects for antibody-resistant viral variants.Thus, we focused on the identification of new antibody combinations and/ornovel bNAbs that restrict pathways of HIV-1 escape.Methods: We screened HIV-1 positive patients for their neutralizingcapacities. Following, we performed single cell sorting and PCR of HIV-1Env-reactive mature B cells of identified elite neutralizers. Found antibodieswere tested for neutralization and binding capacities in vitro. Further, theirantiviral activity was tested in an HIV-1 infected humanized mouse model.Results: Here we report the isolation of antibody 1–18, a VH1–46-encodedCD4 binding site (CD4bs) bNAb identified in an individual ranking among thetop 1% neutralizers of 2,274 HIV-1-infected subjects. Tested on a 119-viruspanel, 1–18 showed to be exceptionally broad and potent with a coverage of97% and a mean IC50 of 0.048 lg/mL, exceeding the activity of most potentCD4bs bNAbs described to-date. A 2.4 A cryo-EM structure of 1–18 bound to anative-like Env trimer revealed that it interacts with HIV-1 env similar to otherCD4bs bNAbs, but includes additional contacts to the V3 loop of the adjacentprotomer. Notably, in vitro, 1–18 maintained activity against viruses carryingmutations associated with escape from VRC01-class bNAbs. Further, its HIV-1env wide escape profile differed critically from other CD4bs bNAbs. Inhumanized mice, monotherapy with 1–18 was sufficient to prevent thedevelopment of viral escape variants that rapidly emerged during treatmentwith other CD4bs bNAbs. Finally, 1–18 overcame classical HIV-1 mutationsthat are driven by VRC01-like bNAbs in vivo.Conclusion: 1–18 is a highly potent and broad bNAb that restricts escape andovercomes frequent CD4bs escape pathways, providing new options for bNAbcombinations to prevent and treat HIV-1 infection." @default.
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• W3027156749 date "2019-11-01" @default.
• W3027156749 modified "2023-09-30" @default.
• W3027156749 title "Novel highly potent CD4bs bNAb with restricted pathway to HIV-1 escape" @default.
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