Journal
NANOMATERIALS
Volume 12, Issue 11, Pages -Publisher
MDPI
DOI: 10.3390/nano12111942
Keywords
dolutegravir; tenofovir; CCR5 monoclonal antibody; nanoformulation; targeting; functional HIV cure
Categories
Funding
- State of Nebraska Cigarette Tax grant, 2017 [LB692]
- NIAID [R01AI117740-01]
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A targeted nanoformulation was designed to block CCR5 expression on T cells and inhibit HIV replication. The nanoformulation showed improved binding affinity to CCR5 and high binding affinity to different types of CCR5+ cells. Short-term prophylaxis study demonstrated that the nanoformulation induced a protective immune phenotype, which could contribute to achieving HIV functional cure.
The C-C motif chemokine receptor-5 (CCR5) expression on the T-cell surface is the prime barrier to HIV/AIDS eradication, as it promotes both active human immunodeficiency virus (HIV)-infection and latency; however, antiretrovirals (ARVs) suppress plasma viral loads to non-detectable levels. Keeping this in mind, we strategically designed a targeted ARVs-loaded nanoformulation that targets CCR5 expressing T-cells (e.g., CD4+ cells). Conceptually, CCR5-blocking and targeted ARV delivery would be a dual protection strategy to prevent HIV infection. For targeting CCR5+ T-cells, the nanoformulation was surface conjugated with anti-CCR5 monoclonal antibodies (CCR5 mAb) and loaded with dolutegravir+tenofovir alafenamide (D+T) ARVs to block HIV replication. The result demonstrated that the targeted-ARV nanoparticle's multimeric CCR5 binding property improved its antigen-binding affinity, prolonged receptor binding, and ARV intracellular retention. Further, nanoformulation demonstrated high binding affinity to CCR5 expressing CD4+ cells, monocytes, and other CCR5+ T-cells. Finally, the short-term pre-exposure prophylaxis study demonstrated that prolonged CCR5 blockage and ARV presence further induced a protective immune phenotype with a boosted T-helper (Th), temporary memory (TM), and effector (E) sub-population. The proof-of-concept study that the targeted-ARV nanoformulation dual-action mechanism could provide a multifactorial solution toward achieving HIV functional cure.
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