Soare et al.
Feb 28, 2020
This study investigates the use of P2X1 receptor antagonists, NF279 and NF449, to block HIV-1 infection, focusing on their ability to inhibit viral fusion.
This study investigates the use of P2X1 receptor antagonists, NF279 and NF449, to block HIV-1 infection, focusing on their ability to inhibit viral fusion. These antagonists were found to effectively reduce HIV-1 infection across a variety of viral strains, acting at the level of viral membrane fusion by interacting with the HIV-1 envelope protein (Env).
Key findings:
Inhibition of Fusion: NF279 and NF449 inhibit HIV-1 fusion by directly targeting the gp120 and gp41 regions of the Env protein, specifically the V1V2 loop of gp120. This prevents HIV-1 from interacting with host cell receptors (CCR5/CXCR4), which is necessary for the fusion process.
Effectiveness Across Clades: Both antagonists demonstrated broad inhibitory activity against different HIV-1 strains, including laboratory-adapted and transmitted/founder strains, with NF449 showing particularly potent activity against X4-tropic HIV-1.
Cross-Interference with Antibody Binding: These antagonists were shown to interfere with the binding of broadly neutralizing antibodies (bNAbs) such as PG9, which targets the V1V2 region, suggesting that NF279 and NF449 may either directly bind to this region or induce conformational changes that block bNAb recognition.
Impact on Viral Tropism: NF279 and NF449 preferentially inhibited X4-tropic strains, with less effect on R5-tropic strains. This indicates potential therapeutic implications for treating infections with specific viral tropisms.
The study concludes that P2X1 antagonists could be promising candidates for novel HIV-1 therapeutics, particularly for inhibiting viral entry through fusion inhibition, and may complement current strategies targeting HIV-1 Env.