Collinearity of protease mutations in HIV-1 samples with high-level protease inhibitor class resistance.
|Title||Collinearity of protease mutations in HIV-1 samples with high-level protease inhibitor class resistance.|
|Publication Type||Journal Article|
|Year of Publication||2013|
|Authors||Babrzadeh F, Varghese V, Pacold M, Liu TF, Nyrén Pål, Schiffer C, Fessel JW, Shafer RW|
|Journal||J Antimicrob Chemother|
|Date Published||2013 Feb|
|Keywords||Drug Resistance, Viral, High-Throughput Nucleotide Sequencing, HIV Protease, HIV Protease Inhibitors, HIV-1, Humans, Microbial Sensitivity Tests, Mutation, Missense, Plasma, RNA, Viral|
OBJECTIVES: To determine whether pan-protease inhibitor (PI)-resistant virus populations are composed predominantly of viruses with resistance to all PIs or of diverse virus populations with resistance to different subsets of PIs. METHODS: We performed deep sequencing of plasma virus samples from nine patients with high-level genotypic and/or phenotypic resistance to all licensed PIs. The nine virus samples had a median of 12 PI resistance mutations by direct PCR Sanger sequencing. RESULTS: For each of the nine virus samples, deep sequencing showed that each of the individual viruses within a sample contained nearly all of the mutations detected by Sanger sequencing. Indeed, a median of 94.9% of deep sequence reads had each of the PI resistance mutations present as a single chromatographic peak in the Sanger sequence. A median of 5.0% of reads had all but one of the Sanger mutations that were not part of an electrophoretic mixture. CONCLUSIONS: The collinearity of PI resistance mutations in the nine virus samples demonstrated that pan-PI-resistant viruses are able to replicate in vivo despite their highly mutated protease enzymes. We hypothesize that the marked collinearity of PI resistance mutations in pan-PI-resistant virus populations results from the unique requirements for multi-PI resistance and the extensive cross-resistance conferred by many of the accessory PI resistance mutations.
|Alternate Journal||J. Antimicrob. Chemother.|