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Three residues in HIV-1 matrix contribute to protease inhibitor susceptibility and replication capacity

Chris M Parry1, Madhavi Kolli, Richard E Myers

  • 1Antiviral Unit, Virus Reference Department, Centre for Infections, Health Protection Agency, 61 Colindale Avenue, London NW95EQ, United Kingdom. chris.parry@hpa.org.uk

Antimicrobial Agents and Chemotherapy
|December 15, 2010
PubMed

Insights

Specific mutations in the HIV Gag matrix protein can significantly reduce protease inhibitor effectiveness. Three key amino acid changes enhance viral replication and drug resistance, impacting treatment strategies.

Area of Science:

  • Virology
  • Molecular Biology
  • Drug Resistance Studies

Background:

  • Limited understanding of non-cleavage site mutations in HIV Gag impacting protease inhibitor susceptibility.
  • Previous work showed Gag mutations, especially in matrix, can restore replication and reduce drug susceptibility with mutant protease.

Purpose of the Study:

  • To identify specific amino acid changes in the HIV Gag matrix protein responsible for altered replication capacity and protease inhibitor susceptibility.
  • To investigate the impact of these matrix mutations on viral fitness and drug resistance.

Main Methods:

  • Analysis of a patient-derived HIV virus with drug resistance.
  • Site-directed mutagenesis to introduce specific amino acid changes (R76K, Y79F, T81A) into the wild-type (WT) matrix protein.
  • Assays to measure replication capacity and protease inhibitor 50% effective concentration (EC₅₀).
  • Sequence covariation analysis and molecular modeling.

Main Results:

  • Three amino acid changes in the matrix protein (R76K, Y79F, T81A) significantly impacted replication capacity and drug susceptibility.
  • Introducing these three changes into WT matrix restored replication capacity of the protease mutant virus.
  • Combinations of these mutations increased replication capacity, with all three showing the greatest effect.
  • These mutations in WT virus caused a 5- to 7-fold increase in protease inhibitor EC₅₀.
  • Sequence covariation and molecular modeling suggested interactions between these positions and altered matrix structure.

Conclusions:

  • Specific mutations within the HIV Gag matrix protein play a crucial role in modulating viral replication and protease inhibitor resistance.
  • The identified mutations (R76K, Y79F, T81A) likely confer resistance through structural changes affecting matrix protein flexibility or integrity.
  • These findings highlight the importance of considering Gag matrix mutations in HIV drug resistance and treatment failure.

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