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Basic Characteristics of Mutations
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Mutation Site
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K158A |
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Mutation Site Sentence
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We compared the effect of MI treatment on the single-cycle infectivity of HIV-1 mutants K158A/I and K227A/I and found that none of these IP6 binding-deficient mutant viruses were inhibited by any of the MIs tested, in contrast to WT (Fig. 2, A and B). |
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Mutation Level
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Amino acid level |
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Mutation Type
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Nonsynonymous substitution |
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Gene/Protein/Region
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Gag |
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Standardized Encoding Gene
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Gag
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Genotype/Subtype
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HIV-1 |
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Viral Reference
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-
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Functional Impact and Mechanisms
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Disease
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HIV Infections
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Immune
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- |
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Target Gene
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-
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Clinical and Epidemiological Correlations
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Clinical Information
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- |
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Treatment
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capsid |
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Location
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- |
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Literature Information
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PMID
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33692109
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Title
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A stable immature lattice packages IP(6) for HIV capsid maturation
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Author
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Mallery DL,Kleinpeter AB,Renner N,Faysal KMR,Novikova M,Kiss L,Wilson MSC,Ahsan B,Ke Z,Briggs JAG,Saiardi A,Bocking T,Freed EO,James LC
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Journal
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Science advances
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Journal Info
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2021 Mar 10;7(11):eabe4716
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Abstract
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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.
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Sequence Data
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-
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