A Mos1 transposase in vivo assay to screen new HIV-1 integrase inhibitors

Area of Science:

• Molecular Biology
• Genetics
• Pharmacology

Background:

• Retroviral integrases and transposases share a catalytic DDE domain.
• In vitro studies indicate HIV-1 integrase inhibitors can affect mariner transposase activity.

Purpose of the Study:

• To investigate the in vivo efficacy of HIV-1 integrase inhibitors against mariner transposase activity using a Drosophila model.
• To evaluate the potential of Drosophila as a screening platform for transposase and integrase inhibitors.

Main Methods:

• Utilized a Drosophila melanogaster strain for quantifying mariner element (Mos1) mobilization via mosaic eye phenotypes.
• Administered HIV-1 integrase inhibitors (raltegravir, dolutegravir) to flies and assessed somatic mobilization rates.
• Quantified mariner transposase gene expression using quantitative PCR (qPCR).

Main Results:

• Raltegravir and dolutegravir treatment resulted in a significant reduction (23-33% and 28-32%, respectively) in somatic mobilization of the mariner element.
• No significant difference in mariner transposase gene expression was observed between treated and control flies, suggesting post-transcriptional inhibition.
• Demonstrated the feasibility of using Drosophila in vivo assays for drug screening.

Conclusions:

• HIV-1 integrase inhibitors exhibit inhibitory effects on mariner transposase activity in vivo.
• Drosophila offers a practical, rapid, and cost-effective in vivo system for screening inhibitors targeting both transposases and retroviral integrases.
• This in vivo approach ensures drug bioavailability and target site delivery, overcoming limitations of in vitro assays.