Apolipoprotein E isoform dependently affects Tat-mediated HIV-1 LTR transactivation

Area of Science:

• Neuroscience
• Virology
• Genetics

Background:

• Apolipoprotein E (ApoE) is crucial for brain lipid transport, with isoforms (ApoE2, ApoE3, ApoE4) influencing HIV-1 infection and neurocognitive disorders.
• HIV-1 Tat protein interacts with LRP1, affecting ApoE uptake and potentially modulating HIV-1 replication and associated neurological complications.

Purpose of the Study:

• To investigate how different Apolipoprotein E (ApoE) isoforms affect HIV-1 Tat-mediated LTR transactivation.
• To explore the therapeutic potential of targeting ApoE interactions in HIV-1 infection and HAND.

Main Methods:

• Utilized U87MG glioblastoma cells with LTR-driven luciferase reporter assays.
• Assessed the impact of LRP1, ApoE isoforms (ApoE2, ApoE3, ApoE4), LRP1 antagonists, siRNA knockdown, ApoE mimetic peptides, and an ApoE4 structure modulator on Tat-mediated HIV-1 LTR transactivation.

Main Results:

• LRP1 antagonism and knockdown significantly restricted Tat-mediated LTR transactivation.
• ApoE4 was least effective in preventing HIV-1 Tat internalization and reducing Tat-mediated LTR transactivation compared to other isoforms.
• ApoE mimetic peptide attenuated transactivation, while an ApoE4 structure modulator enhanced this effect by inducing an ApoE3-like phenotype.

Conclusions:

• Findings elucidate the differential roles of ApoE isoforms in HIV-1 infectivity and HAND prevalence.
• ApoE mimetic peptides and ApoE4 structure modulators show promise as therapeutic strategies against HIV-1 infection and neurocognitive disorders.