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    Three residues in HIV-1 matrix contribute to protease inhibitor susceptibility and replication capacity

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    Authors
    Parry, Chris M.
    Kolli, Madhavi
    Myers, Richard E.
    Cane, Patricia A.
    Schiffer, Celia A.
    Pillay, Deenan
    UMass Chan Affiliations
    Department of Biochemistry and Molecular Pharmacology
    Document Type
    Journal Article
    Publication Date
    2011-03-15
    Keywords
    Cell Line
    Drug Resistance, Viral
    Enzyme-Linked Immunosorbent Assay
    HIV Antigens
    HIV Protease Inhibitors
    HIV-1
    Humans
    Mutagenesis, Site-Directed
    Virus Replication
    gag Gene Products, Human Immunodeficiency Virus
    Biochemistry, Biophysics, and Structural Biology
    Microbiology
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    Link to Full Text
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3067102
    Abstract
    Other than cleavage site mutations, there is little data on specific positions within Gag that impact on HIV protease inhibitor susceptibility. We have recently shown that non-cleavage site mutations in gag, particularly within matrix protein can restore replication capacity and further reduce protease inhibitor drug susceptibility when coexpressed with a drug-resistant (mutant) protease. The matrix protein of this patient-derived virus was studied in order to identify specific changes responsible for this phenotype. Three amino acid changes in matrix (R76K, Y79F, and T81A) had an impact on replication capacity as well as drug susceptibility. Introduction of these three changes into wild-type (WT) matrix resulted in an increase in the replication capacity of the protease mutant virus to a level similar to that achieved by all the changes within the mutant matrix and part of the capsid protein. Pairs of changes to wild-type matrix led to an increased replication capacity of the protease mutant (although less than with all three changes). Having only these three changes to matrix in a wild-type virus (with wild-type protease) resulted in a 5- to 7-fold change in protease inhibitor 50% effective concentration (EC). Individual changes did not have as great an effect on replication capacity or drug susceptibility, demonstrating an interaction between these positions, also confirmed by sequence covariation analysis. Molecular modeling predicts that each of the three mutations would result in a loss of hydrogen bonds within alpha-helix-4 of matrix, leading to the hypothesis that more flexibility within this region or altered matrix structure would account for our findings.
    Source

    Antimicrob Agents Chemother. 2011 Mar;55(3):1106-13. Epub 2010 Dec 13. Link to article on publisher's site

    DOI
    10.1128/AAC.01228-10
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/26005
    PubMed ID
    21149628
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    Link to Article in PubMed

    ae974a485f413a2113503eed53cd6c53
    10.1128/AAC.01228-10
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