Structure based design of cyclically permuted HIV-1 gp120 trimers that elicit neutralizing antibodies

A major goal for HIV-1 vaccine development is an ability to elicit strong and durable broadly neutralizing antibody(bNAb) responses. The trimericenvelope glycoprotein (Env) spikes on HIV-1 are known to contain multiple epitopes that are susceptible to bNAbs isolated from infected individuals. Nonetheless, all trimericand monomeric Env immunogens designed to date have failed to elicit such antibodies. We report the structure-guided design of HIV-1 cyclically permutedgp120 that forms homogeneous, stable trimers, and displays enhanced binding to multiple bNAbs, including VRC01, VRC03, VRCPG04, PGT128, and the quaternary epitope-specific bNAbs PGT145 and PGDM1400. Constructs that were cyclically permutedin the V1 loop region and contained an N-terminal trimerizationdomain to stabilize V1V2-mediated quaternary interactions, showed the highest homogeneity and the best antigenic characteristics. In guinea pigs, a DNA prime-protein boost regimen with these new gp120 trimerimmunogens elicited potent neutralizing antibodyresponses against highly sensitive Tier 1A isolates and weaker neutralizing antibodyresponses with an average titer of about 115 against a panel of heterologous Tier 2 isolates. A modest fraction of the Tier 2 virus neutralizing activity appeared to target the CD4 binding site on gp120. These results suggest that cyclically permutedHIV-1 gp120 trimersrepresent a viable platform in which further modifications may be made to eventually achieve protective bNAb responses.