Mechanistic Insight into Antiretroviral Potency of 2′-Deoxy-2′-β-fluoro-4′-azidocytidine (FNC) with a Long-Lasting Effect on HIV‑1 Prevention

In
preclinical and phase I and II clinical studies, 2′-deoxy-2′-β-fluoro-4′-azidocytidine
(FNC) displays a potent and long-lasting inhibition of HIV-1 infection.
To investigate its mechanism of action, we compared it with the well-documented
lamivudine (3TC). Pharmacokinetic studies revealed that the intracellular
retention of FNC triphosphate in peripheral blood mononuclear cells
was markedly longer than that of the 3TC triphosphate. FNC selectively
enters and is retained in HIV target cells, where it exerts long-lasting
prevention of HIV-1 infection. In addition to inhibition of HIV-1
reverse transcription, FNC also restores A3G expression in CD4+ T cells in FNC-treated HIV-1 patients. FNC binds to the Vif-E3
ubiquitin ligase complex, enabling A3G to avoid Vif-induced ubiquitination
and degradation. These data reveal the mechanisms underlying the superior
anti-HIV potency and long-lasting action of FNC. Our results also
suggest a potential clinical application of FNC as a long-lasting
pre-exposure prophylactic agent capable of preventing HIV infection.