Purinergic receptors are well-established modulators of inflammatory processes, primarily through detection of extracellular
nucleotides that are released by dying or infected cells. Emerging literature has demonstrated that inhibition of these inflammatory receptors can block HIV-1 productive
infection and HIV-1-associated
inflammation. The specificity of receptor type and mechanism of interaction has not yet been determined. Here, we characterize the inhibitory activity of
P2X1 receptor antagonists,
NF279 and
NF449, in cell lines, primary cells, and a variety of HIV-1 envelope (Env) clades.
NF279 and
NF449 blocked productive
infection at the level of viral membrane fusion, with a range of inhibitory activities against different HIV-1 Env isolates. A mutant virus carrying a truncation deletion of the C-terminal tail of HIV-1 Env
glycoprotein 41 (gp41) showed reduced sensitivity to P2X1 antagonists, indicating that the sensitivity of inhibition by these molecules may be modulated by Env conformation. In contrast, a P2X7 antagonist,
A438079, had a limited effect on productive
infection and fusion.
NF279 and
NF449 interfered with the ability of the gp120 variable regions 1 and 2 (V1V2)-targeted
broadly neutralizing antibody PG9 to block productive
infection, suggesting that these drugs may antagonize HIV-1 Env at gp120 V1V2 to block viral membrane fusion. Our observations indicate that P2X1 antagonism can inhibit HIV-1 replication at the level of viral membrane fusion through interaction with Env. Future studies will probe the nature of these compounds in inhibiting HIV-1 fusion and the development of small molecules to block HIV-1 entry via this mechanism.IMPORTANCE While effective treatment can lower the severe morbidity and mortality associated with HIV-1
infection, patients infected with HIV-1 suffer from significantly higher rates of noncommunicable comorbidities associated with chronic
inflammation. Emerging literature suggests a key role for P2X1 receptors in mediating this chronic
inflammation, but the mechanism is still unknown. Here, we demonstrate that HIV-1
infection is reduced by
P2X1 receptor antagonism. This inhibition is mediated by interference with HIV-1 Env and can impact a variety of viral clades. These observations highlight the importance of P2X1 antagonists as potential novel
therapeutics that could serve to block a variety of different viral clades with additional benefits for their anti-inflammatory properties.