Defining rules governing recognition and Fc-mediated effector functions to the HIV-1 co-receptor binding site.

BMC Biology
William D TolbertMarzena Pazgier

Abstract

The binding of HIV-1 Envelope glycoproteins (Env) to host receptor CD4 exposes vulnerable conserved epitopes within the co-receptor binding site (CoRBS) which are required for the engagement of either CCR5 or CXCR4 co-receptor to allow HIV-1 entry. Antibodies against this region have been implicated in the protection against HIV acquisition in non-human primate (NHP) challenge studies and found to act synergistically with antibodies of other specificities to deliver effective Fc-mediated effector function against HIV-1-infected cells. Here, we describe the structure and function of N12-i2, an antibody isolated from an HIV-1-infected individual, and show how the unique structural features of this antibody allow for its effective Env recognition and Fc-mediated effector function. N12-i2 binds within the CoRBS utilizing two adjacent sulfo-tyrosines (TYS) for binding, one of which binds to a previously unknown TYS binding pocket formed by gp120 residues of high sequence conservation among HIV-1 strains. Structural alignment with gp120 in complex with the co-receptor CCR5 indicates that the new pocket corresponds to TYS at position 15 of CCR5. In addition, structure-function analysis of N12-i2 and other CoRBS-specific antibodies ind...Continue Reading

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Citations

Dec 11, 2020·Journal of Virology·Dani VézinaAndrés Finzi
Apr 10, 2021·HIV/AIDS : Research and Palliative Care·Nicholas EvansSharilyn Almodovar
May 22, 2021·Cell Host & Microbe·Jyothi K RajashekarPriti Kumar

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Methods Mentioned

BETA
CoRBS
co-crystallization
PISA
NMR
gel filtration
size exclusion chromatography
transfection
FCS

Software Mentioned

MolProbity
PISA
Dali
Refmac
Phaser
Phenix
ISS VistaVision
lsqkab
WebLogo
CCP4

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