Stabilization of a soluble, native-like trimeric form of an efficiently cleaved Indian HIV-1 clade C envelope glycoprotein
Year: 2017
Type: article
Abstract: Designing an effective HIV-1 envelope glycoprotein (Env) immunogen for elicitation of broadly neutralizing antibodies (bNAbs) is a challenging task because of the high sequence diversity, heavy glycosylation, and inherent meta-stability of Env. Based on the antigenic profile of recently isolated bNAbs, the rational approach to immunogen design is to make a stable version of the Env trimer, which mimics the native trimeric Env present on the viral surface. The SOSIP.664 form of a clade A Env, BG505, yields a homogeneous and well ordered prefusion trimeric form, which maintains structural integrity and desired antigenicity. Following the same approach, we attempted to stabilize a naturally occurring efficiently cleaved clade C Env, namely 4-2.J41, isolated from an Indian patient. Although the SOSIP form of 4-2.J41 failed to produce reasonably well ordered trimers, the 4-2.J41.SOSIP.664 Env could be stabilized in a native-like trimeric form by swapping a domain from BG505 Env to 4-2.J41 Env. Using various biochemical and biophysical means we confirmed that this engineered Env is cleaved, trimeric, and it retains its native-like quaternary conformation exposing mostly broadly neutralizing epitopes. Moreover, introduction of a disulfide bond in the bridging sheet region further stabilized the closed conformation of the Env. Thus, our 4-2.J41.SOSIP.664 Env adds to the increasing pool of potential immunogens for a HIV-1 vaccine, particularly for clade C, which is the most prevalent in India and many other countries. Besides, the approach used to stabilize the 4-2.J41 Env may be used successfully with Envs from other HIV-1 strains as well. Additionally, a soluble native trimeric form of an efficiently cleaved membrane-bound Env, 4-2.J41, may be beneficial for immunization studies using various prime-boost strategies.
Source: Journal of Biological Chemistry
Authors: Shubbir Ahmed, Tripti Shrivastava, Naresh Kumar, Gabriel Ozorowski, Andrew B. Ward, Bimal K. Chakrabarti
Language: English
Topic: HIV Research and Treatment
Subfield: Virology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $1,971
Funders: United States Agency for International Development, Bill and Melinda Gates Foundation, International AIDS Vaccine Initiative, Irish Aid, Department of Biotechnology, Ministry of Science and Technology, India, Department for International Development, Udenrigsministeriet, National Institutes of Health, Direktoratet for Utviklingssamarbeid
OpenAlex ID: W2592395895