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Characterization of a stable HIV-1 B/C recombinant, soluble and trimeric envelope glycoprotein (Env) highly resistant to CD4-induced conformational changes.

Characterization of a stable HIV-1 B/C recombinant, soluble and trimeric envelope glycoprotein (Env) highly resistant to CD4-induced conformational changes.
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Kumar R, Ozorowski G, Kumar V, Holden LG, Shrivastava T, Patil S, Deshpande S, Ward AB, Bhattacharya J,


Kumar R, Ozorowski G, Kumar V, Holden LG, Shrivastava T, Patil S, Deshpande S, Ward AB, Bhattacharya J, (click to view)

Kumar R, Ozorowski G, Kumar V, Holden LG, Shrivastava T, Patil S, Deshpande S, Ward AB, Bhattacharya J,

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The Journal of biological chemistry 2017 07 25() pii 10.1074/jbc.M117.803056

Abstract

The HIV-1 envelope (Env) is a glycoprotein which is a trimer of heterodimer containing gp120 and gp41 subunits, mediates virus entry and is a major target of broadly neutralizing antibodies (bnAbs) developed during infection in some individuals. The engagement of the HIV-1 gp120 glycoprotein to the host CD4 protein triggers conformational changes in gp120 that allows its binding to coreceptors, and is necessary for virus entry to establish infection. Native-like HIV-1 Env immunogens representing distinct clades have been proposed to improve immunogenicity of bnAbs. In the present study, we examined the basis of resistance of an HIV-1 B/C recombinant Env (LT5.J4b12C) to non-neutralizing antibodies targeting CD4-induced Env epitopes in the presence of soluble CD4 (sCD4). Using native polyacrylamide gel shift assay and negative-stain EM, we found that the prefusion conformational state of LT5.J4b12C trimeric Env was largely unaffected in the presence of excess sCD4, with most Env trimers appearing to be in a ligand-free state. This resistance to CD4-induced conformational changes was associated with a lower affinity for CD4. Moreover, the LT5.J4b12C-trimeric Env preferentially bound to the neutralizing antibodies compared to non-neutralizing antibodies. Taken together, we report on an HIV-1 B/C recombinant, native-like trimeric Env protein that is highly resistant to CD4-induced conformational changes, however displays epitopes recognized by a diverse array of bnAbs. Such features make this B/C recombinant trimeric Env a useful addition to the pool of other recently identified native-like HIV-1 Env trimers suitable for use as antigenic bait for bnAb isolation, structural studies and use as potential immunogens.

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