Journal
BRAIN
Volume 130, Issue -, Pages 2011-2023Publisher
OXFORD UNIV PRESS
DOI: 10.1093/brain/awm148
Keywords
HIV; FIV; didanosine; BDNF; mitochondria; neuropathy
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Funding
- NINDS NIH HHS [IR 01NS4626201] Funding Source: Medline
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Antiretroviral toxic neuropathy (ATN) has become a common peripheral neuropathy among HIV/AIDS patients, for which the underlying pathogenesis is uncertain. Indeed, no models exist for ATN that assess the interaction between retroviral infection and antiretroviral therapy. Herein, we developed ex vivo and in vivo models of ATN induced by didanosine (ddI) following infection by the lentivirus, feline immunodeficiency virus (FIV), permitting us to address the working hypothesis that ddI mediates ATN through mitochondrial injury in neurons.We investigated neuronal morphology, neurobehavioural testing, viral load, mitochondrial and neurotrophic factor gene expression after ddI treatment of FIV-infected and uninfected animals or dorsal root ganglia (DRG) cultures. ddI caused concentration-dependent neuronal injury in cultured feline DRGs (P < 0.05), together with reduced viral replication and diminished expression of mitochondrial cytochrome C oxidase subunit I gene (mtCOX 1) and the neurotrophin, brain-derived neurotrophic factor (BDNF). Indeed, BDNF treatment reversed neuronal injury caused by FIV infection in the presence or absence of ddl exposure (P < 0.0). In vivo FIV infection revealed delays in withdrawal latency to a noxious stimulus, which were exacerbated by ddl treatment. Epidermal density of nerve endings was reduced after FIV infection (P < 0.05), especially with ddl treatment. Although viral replication in blood was suppressed in ddl-treated animals (P < 0.05), ddl had a limited effect on viral abundance in DRGs of the same animals. ddl decreased mtCOX I expression in DRG neurons of FIV-infected animals (P < 0.05). BDNF expression was downregulated by ddl in DRG Schwann cells following FIV infection. Thus, ddl treatment during FIV infection resulted in additive pathogenic effects contributing to the development of ATN, which was associated with mitochondrial injury on neurons and reduced BDNF production by Schwann cells in DRGs, highlighting the convergent pathogenic effects that antiretroviral drugs might have in patients with HIV infection.
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