TY  - JOUR
A1  - Schommers, Philipp Frederik
A1  - Grüll, Henning
A1  - Abernathy, Morgan E.
A1  - Tran, My-Kim
A1  - Dingens, Adam S.
A1  - Gristick, Harry B.
A1  - Barnes, Christopher O.
A1  - Schoofs, Till
A1  - Schlotz, Maike
A1  - Vanshylla, Kanika
A1  - Kreer, Christoph
A1  - Weiland, Daniela
A1  - Holtick, Udo
A1  - Scheid, Christof
A1  - Valter, Markus
A1  - Gils, Marit J. van
A1  - Sanders, Rogier W.
A1  - Vehreschild, Jörg Janne
A1  - Cornely, Oliver Andreas
A1  - Lehmann, Clara
A1  - Fätkenheuer, Gerd
A1  - Seaman, Michael S.
A1  - Bloom, Jesse D.
A1  - Bjorkman, Pamela J.
A1  - Klein, Florian
T1  - Restriction of hiv-1 escape by a highly broad and potent neutralizing antibody
T2  - Cell
N2  - Broadly neutralizing antibodies (bNAbs) represent a promising approach to prevent and treat HIV-1 infection. However, viral escape through mutation of the HIV-1 envelope glycoprotein (Env) limits clinical applications. Here we describe 1-18, a new VH1-46-encoded CD4 binding site (CD4bs) bNAb with outstanding breadth (97%) and potency (GeoMean IC50 = 0.048 μg/mL). Notably, 1-18 is not susceptible to typical CD4bs escape mutations and effectively overcomes HIV-1 resistance to other CD4bs bNAbs. Moreover, mutational antigenic profiling uncovered restricted pathways of HIV-1 escape. Of most promise for therapeutic use, even 1-18 alone fully suppressed viremia in HIV-1-infected humanized mice without selecting for resistant viral variants. A 2.5-Å cryo-EM structure of a 1-18-BG505SOSIP.664 Env complex revealed that these characteristics are likely facilitated by a heavy-chain insertion and increased inter-protomer contacts. The ability of 1-18 to effectively restrict HIV-1 escape pathways provides a new option to successfully prevent and treat HIV-1 infection.
KW  - HIV-1
KW  - broadly neutralizing antibodies
KW  - CD4 binding site
KW  - escape mutations
KW  - immunotherapy
KW  - cryogenic electron microscopy
KW  - deep mutational scanning
KW  - mutational antigenic profiling
KW  - HIV-1 escape restriction
KW  - humanized mice
Y1  - 2020
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/53073
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-530735
SN  - 1097-4172
SN  - 0092-8674
N1  - This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
VL  - 180
IS  - 3
SP  - 471
EP  - 489.e22
PB  - Cell Press ; Elsevier
CY  - [Cambridge, Mass.] ; New York, NY
ER  -