Modeling the full length HIV-1 Gag polyprotein reveals the role of its p6 subunit in viral maturation and the effect of non-cleavage site mutations in protease drug resistance. Issue 16 (10th December 2018)

• Record Type: Journal Article
• Authors: Su, Chinh Tran-To; Kwoh, Chee-Keong; Verma, Chandra Shekhar; Gan, Samuel Ken-En
• Is Part Of: Journal of biomolecular structure & dynamics. Volume 36:Issue 16(2018)
• Page Start: 4366
• Page End: 4377
• Publication Date: 2018-12-10
• Subjects: full length HIV-1 Gag structure -- p6 subunit -- allostery -- non-cleavage site mutation -- drug resistance; HAART: highly active antiretroviral therapy -- PIs: protease inhibitors -- MA: matrix -- CA: capsid -- NC: nucleocapsid; Biomolecules -- Periodicals; Molecular structure -- Periodicals; Molecular Biology -- Periodicals; Biomechanics -- Periodicals; 572
• DOI: 10.1080/07391102.2017.1417160
• Languages: English
• ISSNs: 0739-1102

Abstract

Abstract : HIV polyprotein Gag is increasingly found to contribute to protease inhibitor resistance. Despite its role in viral maturation and in developing drug resistance, there remain gaps in the knowledge of the role of certain Gag subunits (e.g. p6), and that of non-cleavage mutations in drug resistance. As p6 is flexible, it poses a problem for structural experiments, and is hence often omitted in experimental Gag structural studies. Nonetheless, as p6 is an indispensable component for viral assembly and maturation, we have modeled the full length Gag structure based on several experimentally determined constraints and studied its structural dynamics. Our findings suggest that p6 can mechanistically modulate Gag conformations. In addition, the full length Gag model reveals that allosteric communication between the non-cleavage site mutations and the first Gag cleavage site could possibly result in protease drug resistance, particularly in the absence of mutations in Gag cleavage sites. Our study provides a mechanistic understanding to the structural dynamics of HIV-1 Gag, and also proposes p6 as a possible drug target in anti-HIV therapy.