Three residues in HIV-1 matrix contribute to protease inhibitor susceptibility and replication capacity
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 PharmacologyDocument Type
Journal ArticlePublication Date
2011-03-15Keywords
Cell LineDrug 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
Metadata
Show full item recordAbstract
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.01228-10Permanent Link to this Item
http://hdl.handle.net/20.500.14038/26005PubMed ID
21149628Related Resources
ae974a485f413a2113503eed53cd6c53
10.1128/AAC.01228-10