Carrier-free micellar CpG interacting with cell membrane for enhanced immunological treatment of HIV-1

Unmethylated CpG motifs activate toll-like receptor 9 (TLR9), leading to sequence-and species-specific immune stimulation. Here, we engineered a CpG oligodeoxyribonucleotide (ODN) with multiple hydrophobic moieties, so-called lipid-modified uracil, which resulted in a facile micelle formation of the stimulant. The self-assembled CpG nanostructure (U4CpG) containing the ODN 2216 sequence was characterized by various spectroscopic and microscopic methods together with molecular dynamics simulations. Next, we evaluated the nanoimmunostimulant for enhancement of anti-HIV immunity. U4CpG treatment induced activation of plasmacytoid dendritic cells (pDCs) and natural killer (NK) cells in healthy human peripheral blood, which produced type I interferons (IFNs) and IFN-gamma in human peripheral blood mononuclear cells (PBMCs). Moreover, we validated the activation and promotion efficacy of U4CpG in patient-derived blood cells, and HIV-1 spread was significantly suppressed by a low dosage of the immunostimulant. Furthermore, U4CpG-treated PBMC cultured medium elicited transcription of latent HIV-1 in U1 cells indicating that U4CpG reversed HIV-1 latency. Thus, the functions of U4CpG in eradicating HIV-1 by enhancing immunity and reversing latency make the material a potential candidate for clinical studies dealing with viral infection.

Automated summary

The study engineered a CpG oligodeoxyribonucleotide with multiple hydrophobic moieties, resulting in a self-assembled CpG nanostructure for enhancing anti-HIV immunity. The treatment activated plasmacytoid dendritic cells and natural killer cells to produce interferons, effectively suppressing HIV-1 spread. Additionally, the nanoimmunostimulant reversed HIV-1 latency, making it a potential candidate for clinical studies on viral infection.