SUMMARY The P2X7 receptor (P2RX7) is an important molecule that functions as a danger sensor, detecting extracellular nucleotides from injured cells and thus signaling an inflammatory program to nearby cells. It is expressed in immune cells and plays important roles in pathogen surveillance and cell-mediated responses to infectious organisms. There is an abundance of literature on the role of P2RX7 in inflammatory diseases and the role of these receptors in host-pathogen interactions. Here, we describe the current knowledge of the role of P2RX7 in the host response to a variety of pathogens, including viruses, bacteria, fungi, protozoa, and helminths. We describe in vitro and in vivo evidence for the critical role these receptors play in mediating and modulating immune responses. Our observations indicate a role for P2X7 signaling in sensing damage-associated molecular patterns released by nearby infected cells to facilitate immunopathology or protection. In this review, we describe how P2RX7 signaling can play critical roles in numerous cells types in response to a diverse array of pathogens in mediating pathogenesis and immunity to infectious agents.
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.
word count: 350 35 Text word count: 6244 36 37 38 39 3 Abstract 40 41 Purinergic receptors detect extracellular ATP and promote inflammatory processes. Emerging literature 42has demonstrated that inhibition of these proinflammatory receptors can block HIV-1 productive infection. The 43 specificity of receptor type and mechanism of interaction has not yet been determined. Here we characterize 44 the inhibitory activity of P2X1 receptor antagonists, NF279 and NF449 in cell lines, primary cells, and in a 45 variety of envelope clades. NF279 and NF449 blocked productive infection at the level of viral membrane 46 fusion with a range of inhibitory activities against different HIV-1 envelopes. A mutant virus carrying a 47 truncation deletion of the C-terminal tail of HIV-1 envelope (Env) glycoprotein 41 (gp41) showed reduced 48 sensitivity to P2X1 antagonists, indicating that the sensitivity of inhibition by these molecules is modulated by 49 Env conformation. By contrast, a P2X7 antagonist, A438079, had limited effect on productive infection and 50 fusion. Inhibition with NF449 interfered with the ability of the V1V2 targeted broadly neutralizing antibody PG9 51 to block productive infection, suggesting that these drugs may antagonize HIV-1 Env at gp120 V1V2 to block 52 viral membrane fusion. Our observations indicate that P2X1 antagonism can inhibit HIV-1 replication at the 53 level of viral membrane fusion through interaction with Env. Future studies will probe the nature of these 54 compounds in inhibiting HIV-1 fusion and in development of a different class of small molecules to block HIV-1 55 entry. 56 57 IMPORTANCE: 58While effective treatment can lower the severe morbidity and mortality associated with HIV-1 infection, patients 59 infected with HIV-1 suffer from significantly higher rates of non-communicable comorbidities associated with 60 chronic inflammation. Emerging literature suggests a key role for P2X1 receptors in mediating this chronic 61 inflammation but the mechanism is still unknown. Here, we demonstrate that HIV-1 infection is reduced by 62 P2X1 receptor antagonism. This inhibition is mediated by interference with HIV-1 Env and can impact a variety 63 of viral clades. These observations highlight the importance of P2X1 antagonists as potential novel 64 therapeutics that could serve to block a variety of different viral clades with additional benefits for their anti-65 inflammatory properties.
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