Collinearity of protease mutations in HIV-1 samples with high-level protease inhibitor class resistance

J Antimicrob Chemother. 2013 Feb;68(2):414-8. doi: 10.1093/jac/dks409. Epub 2012 Oct 19.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Drug Resistance, Viral*
  • HIV Protease / genetics*
  • HIV Protease Inhibitors / pharmacology*
  • HIV-1 / drug effects*
  • HIV-1 / genetics*
  • HIV-1 / isolation & purification
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Microbial Sensitivity Tests
  • Mutation, Missense*
  • Plasma / virology
  • RNA, Viral / genetics

Substances

  • HIV Protease Inhibitors
  • RNA, Viral
  • HIV Protease