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J Biomol Struct Dyn. 2017 Dec 27:1-12. doi: 10.1080/07391102.2017.1417160. [Epub ahead of print]

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.

Author information

1
a Bioinformatics Institute , Agency for Science, Technology, and Research (A*STAR) , Singapore 138671 , Singapore.
2
b School of Computer Science and Engineering , Nanyang Technological University , Singapore 639798 , Singapore.
3
c p53 Laboratory , Agency for Science, Technology, and Research (A*STAR) , Singapore 138648 , Singapore.

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.

KEYWORDS:

CA: capsid; HAART: highly active antiretroviral therapy; MA: matrix; NC: nucleocapsid; PIs: protease inhibitors; allostery; drug resistance; full length HIV-1 Gag structure; non-cleavage site mutation; p6 subunit

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