Structure-guided changes at the V2 apex of HIV-1 clade C trimer enhance elicitation of autologous neutralizing and broad V1V2-scaffold antibodies

Cell Rep. 2022 Mar 1;38(9):110436. doi: 10.1016/j.celrep.2022.110436.

Abstract

HIV-1 clade 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 clade 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-RQH173 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-RQH173 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 clade C trimer capable of eliciting improved neutralizing and V1V2-scaffold antibodies and reveal the importance of the V2 region in tuning this.

Keywords: 173 position; C.1086 trimer; HIV-1 vaccine; V1V2 apex; V1V2-scaffold specific; V2 hotspot; antigenic profile; breadth; immunogen; neutralization; time-dependent BLI.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • AIDS Vaccines*
  • Animals
  • Antibodies, Neutralizing
  • HIV Antibodies
  • HIV Antigens
  • HIV Infections*
  • HIV Seropositivity*
  • HIV-1*
  • Rabbits
  • env Gene Products, Human Immunodeficiency Virus

Substances

  • AIDS Vaccines
  • Antibodies, Neutralizing
  • HIV Antibodies
  • HIV Antigens
  • env Gene Products, Human Immunodeficiency Virus