Probability of N332 glycan occupancy on HIV-1 gp120 modulates sensitivity to broadly neutralizing antibodies.
The glycan shield of the HIV-1 envelope glycoprotein complex (Env), in particular the glycan at position 332 in gp120, is frequently targeted by broadly neutralizing antibodies (bNAbs) isolated from HIV-1-infected individuals. We investigated the role of the second amino acid position of the N332 glycosylation motif Asn-X-Ser in HIV-1 evolution and neutralization sensitivity.



Viral variants harbouring glycosylation motifs with different probabilities of glycan occupancy were tested for their sensitivity to a subset of N332-dependent bNAbs. Furthermore, longitudinal Env sequences of 37 HIV-1 infected individuals were used to analyse the evolution of the N332 glycosylation motif within these individuals. Finally, early Env sequences from 31 historical and 21 contemporaneous seroconverters were compared to analyse this evolution on a population level.



Viral variants with a higher probability of N332 occupancy were more sensitive to neutralization by some N332-dependent bNAbs. Furthermore, the longitudinal analyses revealed an increase in probability of glycan occupancy of the N332 site over time, both within patients, and at the population level over the course of 20 years of HIV-1 epidemic.



These observations suggest that modulation of N332 glycan occupancy by the second amino acid position of the canonical glycosylation motif Asn-X-Ser plays a previously unappreciated role in viral escape from immune responses, and should be considered in Env-based vaccine design.
aDepartment of Medical Microbiology bDepartment of Experimental Immunology, Academic Medical Center, University of Amsterdam, Amsterdam cJanssen Pharmaceuticals, Leiden, The Netherlands dDepartment of Microbiology and Immunology, Weill Medical College, Cornell University, New York City, New York, USA.
Tom L G M
TL
van den Kerkhof
Marit J
MJ
van Gils
Brigitte D
BD
Boeser-Nunnink
Judith A
JA
Burger
Hanneke
H
Schuitemaker
Rogier W
RW
Sanders
D057134:Antibodies, Neutralizing / Q000276:immunology*; D015483:HIV Antibodies / Q000276:immunology*; D015699:HIV Envelope Protein gp120 / Q000737:chemistry* / Q000276:immunology*; D006801:Humans; D057131:Immune Evasion; D011134:Polysaccharides / Q000032:analysis*
D057134:Antibodies, Neutralizing; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D011134:Polysaccharides; C514793:gp120 protein, Human immunodeficiency virus 1