Summary
This project aims to investigate HIV-1 resistance to the capsid inhibitor lenacapavir (LEN) using in vitro and in vivo models, exploring its evolutionary trajectories, impact on viral fitness, and transmissibility.
Deciphering HIV-1 Resistance Pathways against Capsid Inhibitors in vitro and in Humanized Mice
US · IL
NIH
grant
awarded
#nih-1R01AI195459-01A1
What they want
The project will elucidate how HIV-1 acquires increased resistance to LEN through rationally designed, accelerated in vitro evolution approaches, utilizing large-scale mutant libraries combined with multiplex selection and viral adaptation to comprehensively map drug resistance pathways. LEN-resistant variants will be assessed in a humanized mouse model of HIV-1 LEN treatment. The transmission efficiency of LEN-resistant variants will be evaluated in a humanized mouse model of mucosal transmission, and correlates of transmission by LEN-resistant variants will be determined using high-throughput phenotypic assays and in vivo experiments.
Deliverables
- Elucidation of HIV-1 acquisition of increased resistance to LEN
- Mapping of drug resistance pathways
- Assessment of LEN-resistant variants in a humanized mouse model of HIV-1 LEN treatment
- Evaluation of transmission efficiency of LEN-resistant variants in a humanized mouse model of mucosal transmission
- Determination of correlates of transmission by LEN-resistant variants
- Identification of previously unobserved LEN-resistant mutations
Technical requirements
- Rationally designed, accelerated in vitro evolution approaches
- Large-scale mutant libraries
- Multiplex selection and viral adaptation
- Humanized mouse model of HIV-1 LEN treatment
- Humanized mouse model of mucosal transmission
- High-throughput phenotypic assays
- In vivo experiments
