'Royal College of Obstetricians & Gynaecologists (RCOG)'
Abstract
Purpose: Broadly HIV-1 neutralizing antibodies (bNAbs) can suppress viremia
in 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/or
novel bNAbs that restrict pathways of HIV-1 escape.
Methods: We screened HIV-1 positive patients for their neutralizing
capacities. Following, we performed single cell sorting and PCR of HIV-1
Env-reactive mature B cells of identified elite neutralizers. Found antibodies
were tested for neutralization and binding capacities in vitro. Further, their
antiviral activity was tested in an HIV-1 infected humanized mouse model.
Results: Here we report the isolation of antibody 1–18, a VH1–46-encoded
CD4 binding site (CD4bs) bNAb identified in an individual ranking among the
top 1% neutralizers of 2,274 HIV-1-infected subjects. Tested on a 119-virus
panel, 1–18 showed to be exceptionally broad and potent with a coverage of
97% and a mean IC50 of 0.048 lg/mL, exceeding the activity of most potent
CD4bs bNAbs described to-date. A 2.4 Å cryo-EM structure of 1–18 bound to a
native-like Env trimer revealed that it interacts with HIV-1 env similar to other
CD4bs bNAbs, but includes additional contacts to the V3 loop of the adjacent
protomer. Notably, in vitro, 1–18 maintained activity against viruses carrying
mutations associated with escape from VRC01-class bNAbs. Further, its HIV-1
env wide escape profile differed critically from other CD4bs bNAbs. In
humanized mice, monotherapy with 1–18 was sufficient to prevent the
development of viral escape variants that rapidly emerged during treatment
with other CD4bs bNAbs. Finally, 1–18 overcame classical HIV-1 mutations
that are driven by VRC01-like bNAbs in vivo.
Conclusion: 1–18 is a highly potent and broad bNAb that restricts escape and
overcomes frequent CD4bs escape pathways, providing new options for bNAb
combinations to prevent and treat HIV-1 infection