HIV drug nucleoside reverse transcriptase inhibitors as promising anti-inflammation therapeutics by targeting P2X7-dependent large pore formation: one stone for two birds?

Nucleoside reverse transcriptase inhibitors (NRTIs) have been the backbones of HIV therapy since introduced in the late 1980s. These HIV drugs act by blocking the viral reverse transcriptase activity that is crucial in the HIV life cycle. In a recent study published by Science, Fowler et al. (2014) have shown that such antiretroviral agents can inhibit P2X7 receptor (P2X7R)-mediated Alu RNA-induced activation of caspase-1 in retinal pigment epithelial (RPE) cells and ATP-induced activation of caspase1 in macrophage cells, independently of reverse transcriptase inhibition. P2X7R belongs to the ATP-gated ion channel P2XR family and is highly expressed in immune and epithelial cells (North, 2002). P2X7R activation requires submillimolar ATP and the P2X7R is thus well placed as a molecular sensor detecting extracellular ATP, an endogenous danger associated with tissue damage and inflammation. It is firmly established that P2X7R in macrophage cells plays an essential role in mediating ATP-induced assembly of the multi-protein complex NLRP3 inflammasome, activation of caspase-1 and generation of interleukin (IL)-1β, a key proinflammatory cytokine in innate immunity. Such signaling mechanisms, if not resolved in time, can lead to numerous inflammatory conditions. P2X7R antagonists have been passionately exploited as anti-inflammation therapeutics. Several drug discovery programs have discovered a number of structurally novel compounds as P2X7R antagonists with drug-like properties. Such compounds show promising anti-inflammation efficacy in preclinical studies using animal models, but recent clinical trials treating rheumatoid arthritis have been rather disappointing. Noncoding Alu-derived RNAs are accumulated in the retinal pigment epithelium, and Alu RNAs-induced RPE cell death underlies geographic atrophy and choroidal neovascularization, two distinctive forms of aged-related macular degeneration responsible for loss of vision in the elderly people. The same group shows in another study that Alu RNAs can stimulate the P2X7R activity via undefined mechanisms to activate the NLRP3 inflammasome and caspase-1. In this recent study, they provide evidence to show that NRTIs inhibit P2X7R-mediated activation of caspase-1 in RPE cells and in LPS-primed macrophage cells induced by Alu RNAs and ATP, respectively. Furthermore, they have demonstrated that such HIV drugs exhibit significant anti-inflammation efficacy in mouse models of geographic atrophy, choroidal neovascularization, graft-vs-host diseases, and sterile liver inflammation. This is a truly exciting finding as many clinically proved HIV drugs can be readily tested as anti-inflammation therapeutics. P2X7R, like all other P2XRs, functions as a channel that opens upon brief stimulation to permeate small physiological cations (North, 2002). However, it is known from the conception of the P2XR research that P2X7R is functionally exceptional; prolonged activation can induce a large pore that passes molecules in size of up to 900 Da and can eventually lead to cell death, thus formerly named the cytolytic P2Z receptor (Surprenant et al., 1996). Nearly 20 years on from identification as the last member of the P2XR family, the molecular mechanisms underpinning such striking plasticity in permeability is still puzzling. A recent study unequivocally demonstrates that the P2X7R small cationic channel can dilate to become the large pore (Browne et al., 2013). There is compelling evidence to support that P2X7R-dependent formation of the intrinsic large pore in macrophage cells engages pannexin-1, and particularly requires an interaction of pannexin-1 with the unique C-terminus of the P2X7R (Pelegrin and Surprenant, 2006; Sorge et al., 2012). The genes encoding the mammalian P2X7Rs and particularly human P2X7R are prolific with non-synonymous single nucleotide polymorphisms (NS-SNP), and NS-SNP mutations can significantly alter the small cationic channel, the large pore, or both functionalities. For example, the NS-SNP P451L mutation in the C-terminus of the mouse P2X7R totally abolishes the large pore formation without altering the small