TY - JOUR
T1 - Stabilization of the V2 loop improves the presentation of V2 loop associated broadly neutralizing antibody epitopes on HIV-1 envelope trimers
AU - de Taeye, Steven W.
AU - Go, Eden P.
AU - Sliepen, Kwinten
AU - de la Peña, Alba Torrents
AU - Badal, Kimberly
AU - Medina-Ramírez, Max
AU - Lee, Wen-Hsin
AU - Desaire, Heather
AU - Wilson, Ian A.
AU - Moore, John P.
AU - Ward, Andrew B.
AU - Sanders, Rogier W.
N1 - © 2019 de Taeye et al.
PY - 2019/4/5
Y1 - 2019/4/5
N2 - A successful HIV-1 vaccine will likely need to elicit broadly neutralizing antibodies (bNAbs) that target the envelope glycoprotein (Env) spike on the virus. Native-like recombinant Env trimers of the SOSIP design now serve as a platform for achieving this challenging goal. However, SOSIP trimers usually do not bind efficiently to the inferred germline precursors of bNAbs (gl-bNAbs). We hypothesized that the inherent flexibilities of the V1 and V2 variable loops in the Env trimer contribute to the poor recognition of gl-bNAb epitopes at the trimer apex that extensively involve V2 residues. To reduce local V2 flexibility and improve the binding of V2-dependent bNAbs and glbNAbs, we designed BG505 SOSIP.664 trimer variants containing newly created disulfide bonds intended to stabilize the V2 loop in an optimally antigenic configuration. The first variant, I184C/E190C, contained a new disulfide bond within the V2 loop, whereas the second variant, E153C/R178C, had a new disulfide bond that cross-linked V2 and V1. The resulting engineered native-like trimer variants were both more reactive with and were neutralized by V2 bNAbs and gl-bNAbs, a finding that may be valuable in the design of germline targeting and boosting trimer immunogens to create an antigenic conformation optimal for HIV vaccine development.
AB - A successful HIV-1 vaccine will likely need to elicit broadly neutralizing antibodies (bNAbs) that target the envelope glycoprotein (Env) spike on the virus. Native-like recombinant Env trimers of the SOSIP design now serve as a platform for achieving this challenging goal. However, SOSIP trimers usually do not bind efficiently to the inferred germline precursors of bNAbs (gl-bNAbs). We hypothesized that the inherent flexibilities of the V1 and V2 variable loops in the Env trimer contribute to the poor recognition of gl-bNAb epitopes at the trimer apex that extensively involve V2 residues. To reduce local V2 flexibility and improve the binding of V2-dependent bNAbs and glbNAbs, we designed BG505 SOSIP.664 trimer variants containing newly created disulfide bonds intended to stabilize the V2 loop in an optimally antigenic configuration. The first variant, I184C/E190C, contained a new disulfide bond within the V2 loop, whereas the second variant, E153C/R178C, had a new disulfide bond that cross-linked V2 and V1. The resulting engineered native-like trimer variants were both more reactive with and were neutralized by V2 bNAbs and gl-bNAbs, a finding that may be valuable in the design of germline targeting and boosting trimer immunogens to create an antigenic conformation optimal for HIV vaccine development.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85064415332&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/30728245
U2 - https://doi.org/10.1074/jbc.RA118.005396
DO - https://doi.org/10.1074/jbc.RA118.005396
M3 - Article
C2 - 30728245
SN - 0021-9258
VL - 294
SP - 5616
EP - 5631
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 14
ER -