In:
Science Advances, American Association for the Advancement of Science (AAAS), Vol. 7, No. 11 ( 2021-03-12)
Kurzfassung:
HIV virion assembly begins with the construction of an immature lattice consisting of Gag hexamers. Upon virion release, protease-mediated Gag cleavage leads to a maturation event in which the immature lattice disassembles and the mature capsid assembles. The cellular metabolite inositiol hexakisphosphate (IP 6 ) and maturation inhibitors (MIs) both bind and stabilize immature Gag hexamers, but whereas IP 6 promotes virus maturation, MIs inhibit it. Here we show that HIV is evolutionarily constrained to maintain an immature lattice stability that ensures IP 6 packaging without preventing maturation. Replication-deficient mutant viruses with reduced IP 6 recruitment display increased infectivity upon treatment with the MI PF46396 (PF96) or the acquisition of second-site compensatory mutations. Both PF96 and second-site mutations stabilise the immature lattice and restore IP 6 incorporation, suggesting that immature lattice stability and IP 6 binding are interdependent. This IP 6 dependence suggests that modifying MIs to compete with IP 6 for Gag hexamer binding could substantially improve MI antiviral potency.
Materialart:
Online-Ressource
ISSN:
2375-2548
DOI:
10.1126/sciadv.abe4716
Sprache:
Englisch
Verlag:
American Association for the Advancement of Science (AAAS)
Publikationsdatum:
2021
ZDB Id:
2810933-8