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Peer-reviewedCC BY 4.0Scientific Reports

Distal amino-acid substitutions contribute to HIV protease inhibitor resistance as directly as proximal amino-acid substitutions

  • Debananda Das
  • Hironori Hayashi
  • Yuki Takamatsu
  • Manabu Aoki
  • Haydar Bulut
  • Ravikiran S. Yedidi
  • Kazutaka Murayama
  • Kazuya Hasegawa
  • Arun K. Ghosh
  • Hiroaki Mitsuya
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Abstract

There are two categories of drug-resistance-associated amino-acid substitutions responsible for causing drug resistance in HIV-1 protease: (i) major and (ii) minor substitutions. In general, major substitutions mostly arise early during treatment, reduce susceptibility to the drug and are mostly proximal to the protease active site. Minor substitutions mostly arise later, may provide incremental resistance and/or improve viral fitness and are often distal from the active site. However, no precise definitions of such two categories exist. Herein, using X-ray crystallography and molecular dynamics (MD) simulations we examined the structural basis of antiviral resistance of HIV DRV R p51 , an HIV-1 variant that has three proximal (V32I, V82I, I84V) and eleven distal substitutions (L10I/I15V/K20R/L24I/L33F/M36I/ M46L/ I54M/L63P/K70Q/L89M) in the protease region (PR p51 ), and has high resistance against a protease inhibitor darunavir (DRV), but not against another protease inhibitor GRL142. MD demonstrated that the proximal and distal substitutions work in concert to carry out structural changes that result in larger perturbations in inter-residue distances and active site cavity volume for DRV-PR p51 over DRV-PR wt compared to GRL142-PR p51 over GRL142-PR wt . These results provided a rationale for the different resistance profiles of DRV and GRL142. The results also suggest reconsideration of the simplistic classification of substitutions as either major or minor.

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Cite

BibTeXRIS
BibTeX
@article{das2026distal,
  title = {{Distal amino-acid substitutions contribute to HIV protease inhibitor resistance as directly as proximal amino-acid substitutions}},
  author = {Debananda Das and Hironori Hayashi and Yuki Takamatsu and Manabu Aoki and Haydar Bulut and Ravikiran S. Yedidi and Kazutaka Murayama and Kazuya Hasegawa and Arun K. Ghosh and Hiroaki Mitsuya},
  journal = {Scientific Reports},
  year = {2026},
  month = oct,
  doi = {10.1038/s41598-026-64620-7},
  url = {https://www.nature.com/articles/s41598-026-64620-7},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Distal amino-acid substitutions contribute to HIV protease inhibitor resistance as directly as proximal amino-acid substitutions
AU  - Debananda Das
AU  - Hironori Hayashi
AU  - Yuki Takamatsu
AU  - Manabu Aoki
AU  - Haydar Bulut
AU  - Ravikiran S. Yedidi
AU  - Kazutaka Murayama
AU  - Kazuya Hasegawa
AU  - Arun K. Ghosh
AU  - Hiroaki Mitsuya
PY  - 2026
DA  - 2026/10/05
JO  - Scientific Reports
DO  - 10.1038/s41598-026-64620-7
UR  - https://www.nature.com/articles/s41598-026-64620-7
AB  - There are two categories of drug-resistance-associated amino-acid substitutions responsible for causing drug resistance in HIV-1 protease: (i) major and (ii) minor substitutions. In general, major substitutions mostly arise early during treatment, reduce susceptibility to the drug and are mostly proximal to the protease active site. Minor substitutions mostly arise later, may provide incremental resistance and/or improve viral fitness and are often distal from the active site. However, no precise definitions of such two categories exist. Herein, using X-ray crystallography and molecular dynamics (MD) simulations we examined the structural basis of antiviral resistance of HIV DRV R p51 , an HIV-1 variant that has three proximal (V32I, V82I, I84V) and eleven distal substitutions (L10I/I15V/K20R/L24I/L33F/M36I/ M46L/ I54M/L63P/K70Q/L89M) in the protease region (PR p51 ), and has high resistance against a protease inhibitor darunavir (DRV), but not against another protease inhibitor GRL142. MD demonstrated that the proximal and distal substitutions work in concert to carry out structural changes that result in larger perturbations in inter-residue distances and active site cavity volume for DRV-PR p51 over DRV-PR wt compared to GRL142-PR p51 over GRL142-PR wt . These results provided a rationale for the different resistance profiles of DRV and GRL142. The results also suggest reconsideration of the simplistic classification of substitutions as either major or minor.
SN  - 2045-2322
ER  -