Designed cyclic permutants of HIV-1 gp120: implications for envelope trimer structure and immunogen design

Biochemistry
Piyali SahaRaghavan Varadarajan

Abstract

Most HIV-1 broadly neutralizing antibodies are directed against the gp120 subunit of the env surface protein. Native env consists of a trimer of gp120-gp41 heterodimers, and in contrast to monomeric gp120, preferentially binds CD4 binding site (CD4bs)-directed neutralizing antibodies over non-neutralizing ones. Some cryo-electron tomography studies have suggested that the V1V2 loop regions of gp120 are located close to the trimer interface. We have therefore designed cyclically permuted variants of gp120 with and without the h-CMP and SUMO2a trimerization domains inserted into the V1V2 loop. h-CMP-V1cyc is one such variant in which residues 153 and 142 are the N- and C-terminal residues, respectively, of cyclically permuted gp120 and h-CMP is fused to the N-terminus. This molecule forms a trimer under native conditions and binds CD4 and the neutralizing CD4bs antibodies b12 with significantly higher affinity than wild-type gp120. It binds non-neutralizing CD4bs antibody F105 with lower affinity than gp120. A similar derivative, h-CMP-V1cyc1, bound the V1V2 loop-directed broadly neutralizing antibodies PG9 and PG16 with ∼20-fold higher affinity than wild-type JRCSF gp120. These cyclic permutants of gp120 are properly folded and ...Continue Reading

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Citations

Dec 27, 2013·Science China. Life Sciences·Dongxing GuoLinqi Zhang
Jun 4, 2014·Biochimica Et Biophysica Acta·Ujjwal RathoreRaghavan Varadarajan
Apr 30, 2016·Scientific Reports·Mona RiemenschneiderDominik Heider
Nov 24, 2016·The Journal of Biological Chemistry·Sannula KesavardhanaRaghavan Varadarajan
Nov 11, 2020·Proceedings of the National Academy of Sciences of the United States of America·Rohini DattaRaghavan Varadarajan

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