Investigating Mechanisms of Nucleoside Reverse Transcriptase Inhibitor Induced Sensory Neuropathy
The success of antiretroviral therapy (ART) has generally improved the survival of HIV-infected patients. However, patients on ART whose HIV disease is well controlled show peripheral sensory neuropathy (PSN), supporting the idea that the ART may cause PSN. Although the nucleoside reverse transcriptase inhibitors (NRTIs) used in the ART are thought to contribute to PSN, the mechanisms underlying the PSN induced by NRTIs are unclear. This is partly due to the lack of a good model for mechanistic investigations. In this study, we developed a Drosophila model and modified a mouse model of NRTI-induced PSN that recapitulates the salient features observed in patients undergoing ART: PSN and nociception sensitization. Furthermore, through modified expression screening of both genomic and mitochondrial genes we have identified several effectors that inhibit or exacerbate the NRTI-induced PSN phenotype. The most promising candidate identified was nicotinamide mononucleotide adenylyltransferease (NMNAT) which at increased levels inhibits the NRTI-induced PSN and nociception sensitization in our model. Further characterization revealed that ubiquitous upregulation of catalytically competent NMNAT was required for its neuroprotection against NRTI-induced PSN. From this, we utilized the Drosophila and mouse models to investigate the effects of NAD+ precursor coadministration with NRTI. The mouse model allowed for extended testing from which we determined vitamin B3 exhibits potential to both inhibit and rescue NRTI-induced PSN. Therefore, our models developed here provide a robust platform to elucidate the pathogenic mechanisms of painful PSN induced by chronic exposure to NRTIs, and our findings provide insight into the effectors of NRTI-induced PSN and potentially provide vitamin B3 as a readily implementable, accessible, and inexpensive cotreatment with ART that could improve the quality of life for patients.