TY - JOUR
T1 - Structural elements of primary CCR5-using HIV-1 gp120 proteins influencing sensitivity and resistance to the broadly neutralizing monoclonal antibody b12
AU - Sterjovski, Jasminka
AU - Churchill, Melissa J.
AU - Ellett, Anne
AU - Wesselingh, Steve L.
AU - Ramsland, Paul A.
AU - Gorry, Paul R.
N1 - Funding Information:
We thank J. Sodroski for providing JR-CSF, ADA and ΔKS Env plasmids, and for providing pCMVΔP1ΔenvpA and pHIV-1Luc plasmids. We thank D. Kabat for providing JC53 cells, and D. Burton for providing the b12 mAb. The following reagent was obtained through the NIH AIDS Research and Reference Reagent Program, Division of AIDS, NIAID, NIH: Catalog #3957, HIV-Ig from NABI and NHLBI. This study was supported, in part, by grants from the Australian National Health and Medical Research Council (NHMRC) to PRG, MJC and SLW (#603708, #1006534). PAR is the Sir Zelman Cowen Senior Research Fellow (Sir Zelman Cowen Fellowship Fund, Burnet Institute). PRG is the recipient of an Australian NHMRC Level 2 Biomedical Career Development Award. The authors gratefully acknowledge the contribution to this work of the Victorian Operational Infrastructure Support Program received by the Burnet Institute.
PY - 2012/10/25
Y1 - 2012/10/25
N2 - Structure-guided approaches to HIV-1 vaccine design depend on knowledge of the presentation of neutralizing epitopes on gp120, such as the epitope for the broadly neutralizing mAb b12. Here, we characterized predicted three-dimensional structures of functionally diverse gp120 proteins in their b12-bound conformation, to better understand the gp120 determinants that expose or occlude the b12 epitope. Mapping the gp120-b12 binding interface identified amino acid polymorphisms within the C2, C3, C4 and V5 regions of gp120 associated with augmented b12 binding, and importantly, identified residues in the b12-exclusive binding domain of gp120 that are important for b12 neutralization resistance. Structural studies suggest that these b12 resistance variants promote reduced conformational flexibility in the b12 recognition site, which we show involves structural alterations within the gp120 CD4 binding loop and the V4 loop. Together, our studies provide new mechanistic insights into the gp120 determinants influencing sensitivity and resistance to HIV-1 neutralization by b12.
AB - Structure-guided approaches to HIV-1 vaccine design depend on knowledge of the presentation of neutralizing epitopes on gp120, such as the epitope for the broadly neutralizing mAb b12. Here, we characterized predicted three-dimensional structures of functionally diverse gp120 proteins in their b12-bound conformation, to better understand the gp120 determinants that expose or occlude the b12 epitope. Mapping the gp120-b12 binding interface identified amino acid polymorphisms within the C2, C3, C4 and V5 regions of gp120 associated with augmented b12 binding, and importantly, identified residues in the b12-exclusive binding domain of gp120 that are important for b12 neutralization resistance. Structural studies suggest that these b12 resistance variants promote reduced conformational flexibility in the b12 recognition site, which we show involves structural alterations within the gp120 CD4 binding loop and the V4 loop. Together, our studies provide new mechanistic insights into the gp120 determinants influencing sensitivity and resistance to HIV-1 neutralization by b12.
KW - B12
KW - Gp120
KW - HIV-1
KW - Neutralization
KW - Structure
UR - http://www.scopus.com/inward/record.url?scp=84865303160&partnerID=8YFLogxK
U2 - 10.1016/j.virol.2012.06.024
DO - 10.1016/j.virol.2012.06.024
M3 - Article
C2 - 22818780
AN - SCOPUS:84865303160
SN - 0042-6822
VL - 432
SP - 394
EP - 404
JO - Virology
JF - Virology
IS - 2
ER -