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Resistance to Second-Generation HIV-1 Maturation Inhibitors
Emiko Urano1, Uddhav Timilsina2, Justin A Kaplan1
1Virus-Cell Interaction Section, HIV Dynamics and Replication Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, USA.
Journal of Virology
|December 21, 2018
Summary
New HIV-1 maturation inhibitors show potent activity against resistant strains. Researchers identified specific mutations conferring resistance, offering insights into drug mechanisms and guiding future HIV-1 treatment development.
Area of Science:
- Virology
- Drug Discovery
- Molecular Biology
Background:
- Bevirimat (BVM), a betulinic acid-based compound, inhibits HIV-1 maturation by blocking Gag polyprotein processing, specifically the cleavage of the capsid-spacer peptide 1 (CA-SP1) intermediate.
- Resistance to BVM emerged due to mutations near the CA-SP1 cleavage site, leading to the discontinuation of its clinical development.
- Second-generation BVM analogs have been developed with improved potency and broader activity against HIV-1.
Purpose of the Study:
- To investigate the efficacy of second-generation bevirimat analogs against HIV-1 strains with existing BVM resistance mutations.
- To identify novel mutations conferring resistance to these advanced maturation inhibitors through de novo selection experiments.
- To gain insights into the mechanisms of resistance to second-generation HIV-1 maturation inhibitors.
Main Methods:
- Performed de novo selection experiments using subtype B and subtype C HIV-1 to identify resistance mutations to second-generation bevirimat analogs.
- Sequenced viral clones to pinpoint specific amino acid substitutions in Gag (SP1 and CA domains) associated with resistance.
- Assessed the impact of identified mutations on HIV-1 susceptibility to maturation inhibitors and analyzed CA-SP1 processing kinetics.
Main Results:
- Second-generation BVM analogs effectively inhibited viral clones with BVM resistance mutations near the C terminus of CA.
- Resistance mutations identified in subtype B included SP1-A1V and CA-P157A; in subtype C, mutations included CA-V230M, SP1-A1V, SP1-S5N, and SP1-G10R.
- These resistance-conferring mutations occurred at highly conserved positions within the Gag protein and resulted in modest to high-level resistance, generally without significantly altering CA-SP1 processing kinetics.
Conclusions:
- Second-generation bevirimat analogs demonstrate potent activity against HIV-1 strains resistant to earlier compounds.
- The identified mutations provide a detailed map of resistance mechanisms for novel maturation inhibitors.
- These findings are crucial for understanding HIV-1 resistance pathways and for the rational design of future antiretroviral therapies.
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