Magnetoelectric Extracellular Vesicle Latency-Targeting (MELT) Nanotherapeutic for the Block-Lock-and-Kill HIV Eradication Strategy
Background: Human immunodeficiency virus (HIV) establishes latent infections in cellular reservoirs, including microglia. HC69 cells, a microglial model of HIV latency, contain an HIV promoter long terminal repeat (LTR)-GFP reporter and were used for testing the efficacy of a two-step magnetoelectri...
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| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2025-01-01
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| Series: | Biomedicines |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2227-9059/13/1/147 |
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| Summary: | Background: Human immunodeficiency virus (HIV) establishes latent infections in cellular reservoirs, including microglia. HC69 cells, a microglial model of HIV latency, contain an HIV promoter long terminal repeat (LTR)-GFP reporter and were used for testing the efficacy of a two-step magnetoelectric nanoparticle (MENP) and extracellular vesicle (xEV) latency-targeting (MELT) nanotherapeutic. GFP expression in HC69 at rest is low (GFP<sup>Lo</sup>), and upon exposure to LTR, transcription-activating agents (i.e., TNF-α) are induced to be high expressing (GFP<sup>Hi</sup>). Methods: The first step of MELT utilized ZL0580, an HIV Tat inhibitor loaded into EVs (80%) via incubation. ZL0580-EVs were taken up by GFP<sup>Lo</sup> and blocked LTR transcriptional reactivation by 50% and were 90% less toxic than ZL0580 alone. The second step in MELT involved conjugation of monomethyl auristatin E (MMAE) to MENPs. HPLC measurements showed 80% MMAE attachment to MENPs. Flow cytometry-based measurements of the membrane potential indicated that the membranes of GFP<sup>Hi</sup> HC69 were 60% more polarized than GFP<sup>Lo</sup> HC69 cells. More MMAE–MENPs were internalized by GFP<sup>Lo</sup> HC69. Results: Using a mixed-cell blood–brain barrier (BBB) Transwell model, we demonstrated that 20% of MELT crossed the BBB, was taken up by HC69 cells, and reduced LTR reactivation by 10%. Conclusions: Overall, this study demonstrated that MELT can potentially be utilized as a nanotherapeutic to target HIV latency in microglia. |
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| ISSN: | 2227-9059 |