Investigating Mechanisms of Nucleoside Reverse Transcriptase Inhibitor Induced Sensory Neuropathy

Bush, Keegan Michael

Investigating Mechanisms of Nucleoside Reverse Transcriptase Inhibitor Induced Sensory Neuropathy

dc.creator	Bush, Keegan Michael
dc.date.accessioned	2023-12-05T15:27:08Z
dc.date.available	2023-12-05T15:27:08Z
dc.date.created	2021-08
dc.date.issued	August 2021
dc.date.submitted	August 2021
dc.date.updated	2023-12-05T15:27:08Z
dc.description.abstract	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.
dc.format.mimetype	application/pdf
dc.identifier.uri
dc.identifier.uri	https://hdl.handle.net/2152.3/12209
dc.subject	Biology, Neuroscience
dc.subject.other	antiretroviral therapy (ART)
dc.subject.other	peripheral sensory neuropathy (PSN)
dc.subject.other	nucleoside reverse transcriptase inhibitors (NRTIs)
dc.subject.other	nicotinamide mononucleotide adenylyltransferease (NMNAT)
dc.title	Investigating Mechanisms of Nucleoside Reverse Transcriptase Inhibitor Induced Sensory Neuropathy
dc.type	Thesis
dc.type.material	text
thesis.degree.department	Neuroscience
thesis.degree.grantor	The University of Texas Medical Branch at Galveston
thesis.degree.name	Neuroscience (Doctoral)