Design and structure of two HIV-1 clade C SOSIP.664 trimers that increase the arsenal of native-like Env immunogens.

TitleDesign and structure of two HIV-1 clade C SOSIP.664 trimers that increase the arsenal of native-like Env immunogens.
Publication TypeJournal Article
Year of Publication2015
AuthorsJulien J-P, Lee J H, Ozorowski G, Hua Y, de la Peña ATorrents, de Taeye SW, Nieusma T, Cupo A, Yasmeen A, Golabek M, Pugach P, Klasse PJ, Moore JP, Sanders RW, Ward AB, Wilson IA
JournalProc Natl Acad Sci U S A
Date Published09/22/2015
ISSN1091-6490
Abstract

A key challenge in the quest toward an HIV-1 vaccine is design of immunogens that can generate a broadly neutralizing antibody (bnAb) response against the enormous sequence diversity of the HIV-1 envelope glycoprotein (Env). We previously demonstrated that a recombinant, soluble, fully cleaved SOSIP.664 trimer based on the clade A BG505 sequence is a faithful antigenic and structural mimic of the native trimer in its prefusion conformation. Here, we sought clade C native-like trimers with comparable properties. We identified DU422 and ZM197M SOSIP.664 trimers as being appropriately thermostable (Tm of 63.4 °C and 62.7 °C, respectively) and predominantly native-like, as determined by negative-stain electron microscopy (EM). Size exclusion chromatography, ELISA, and surface plasmon resonance further showed that these trimers properly display epitopes for all of the major bnAb classes, including quaternary-dependent, trimer-apex (e.g., PGT145) and gp120/gp41 interface (e.g., PGT151) epitopes. A cryo-EM reconstruction of the ZM197M SOSIP.664 trimer complexed with VRC01 Fab against the CD4 binding site at subnanometer resolution revealed a striking overall similarity to its BG505 counterpart with expected local conformational differences in the gp120 V1, V2, and V4 loops. These stable clade C trimers contribute additional diversity to the pool of native-like Env immunogens as key components of strategies to induce bnAbs to HIV-1.

DOI10.1073/pnas.1507793112
Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID26372963
Grant ListR01 AI084817 / AI / NIAID NIH HHS / United States
UM1 AI100663 / AI / NIAID NIH HHS / United States
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