Three residues in HIV-1 matrix contribute to protease inhibitor susceptibility and replication capacity
Department of Biochemistry and Molecular Pharmacology
Medical Subject Headings
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
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.
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Citation: Antimicrob Agents Chemother. 2011 Mar;55(3):1106-13. Epub 2010 Dec 13. Link to article on publisher's site
Parry, Chris M.; Kolli, Madhavi; Myers, Richard E.; Cane, Patricia A.; Schiffer, Celia A.; and Pillay, Deenan, "Three residues in HIV-1 matrix contribute to protease inhibitor susceptibility and replication capacity" (2011). Biochemistry and Molecular Pharmacology Publications and Presentations. 135.