|Title||Structural characterization of cleaved, soluble HIV-1 envelope glycoprotein trimers.|
|Publication Type||Journal Article|
|Year of Publication||2013|
|Authors||Khayat R, Lee J H, Julien J-P, Cupo A, Klasse P J, Sanders RW, Moore JP, Wilson IA, Ward AB|
Human immunodeficiency virus type 1 (HIV-1) infection is a significant global public health problem for which development of an effective prophylactic vaccine remains a high scientific priority. Many concepts for a vaccine are focused on induction of appropriate titers of broadly neutralizing antibodies (bNAbs) against the viral envelope (Env) glycoproteins gp120 and gp41, but no immunogen has yet accomplished this goal in animals or humans. One approach to induction of bNAbs is to design soluble, trimeric mimics of the native viral Env trimer. Here, we describe structural studies by negative-stain electron microscopy of several variants of soluble Env trimers based on the KNH1144 subtype A sequence. These Env trimers are fully cleaved between the gp120 and gp41 components and stabilized by specific amino acid substitutions. We also illustrate the structural consequences of deletion of the V1/V2 and V3 variable loops from gp120 and the membrane-proximal external region (MPER) from gp41. All of these variants adopt a trimeric configuration that appropriately mimics native Env spikes, including the CD4 receptor-binding site and the epitope for the VRC PG04 bNAb. These cleaved, soluble trimer designs can be adapted for use with multiple different env genes for both vaccine and structural studies.
|Alternate Journal||J. Virol.|
|PubMed Central ID||PMC3754114|
|Grant List||HIVRAD P01 AI82362 / AI / NIAID NIH HHS / United States |
P30 AI036214 / AI / NIAID NIH HHS / United States
R01 AI84817 / AI / NIAID NIH HHS / United States
R37 AI36082 / AI / NIAID NIH HHS / United States
RR017573 / RR / NCRR NIH HHS / United States
UM1 AI100663 / AI / NIAID NIH HHS / United States
/ / Canadian Institutes of Health Research / Canada
Structural characterization of cleaved, soluble HIV-1 envelope glycoprotein trimers.