Journal
CELL REPORTS
Volume 38, Issue 9, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2022.110436
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Funding
- National Institutes of Health (NIH, United States) [U19 AI109633, R01 AI140868]
- Office of research Infrastructure Programs (ORIP/NIH) [P51 OD011132]
- Bill and Melinda Gates Foundation through the Collaboration for AIDS Vaccine Discovery (CAVD) grant [OPP1115782]
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HIV-1 Glade C envelope immunogens that elicit both neutralizing and non-neutralizing V1V2-scaffold-specific antibodies are urgently needed. This study introduces structure-guided changes and consensus-C-sequence-guided optimizations to generate a stabilized Glade C trimer capable of eliciting improved neutralizing and V1V2-scaffold antibodies. The results highlight the importance of the V2 region in antibody response.
HIV-1 Glade C envelope immunogens that elicit both neutralizing and non-neutralizing V1V2-scaffold-specific antibodies (protective correlates from RV144 human trial) are urgently needed due to the prevalence of this Glade in the most impacted regions worldwide. To achieve this, we introduce structure-guided changes followed by consensus-C-sequence-guided optimizations at the V2 region to generate UFO-v2-RQH(173) trimer. This improves the abundance of well-formed trimers. Following the immunization of rabbits, the wild-type protein fails to elicit any autologous neutralizing antibodies, but UFO-v2-RQH(173) elicits both autologous neutralizing and broad V1V2-scaffold antibodies. The variant with a 173Y modification in the V2 region, most prevalent among HIV-1 sequences, shows decreased ability in displaying a native-like V1V2 epitope with time in vitro and elicited antibodies with lower neutralizing and higher V1V2-scaffold activities. Our results identify a stabilized Glade C trimer capable of eliciting improved neutralizing and V1V2-scaffold antibodies and reveal the importance of the V2 region in tuning this.
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