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 I) and the
neurotrophin,
brain-derived neurotrophic factor (
BDNF). Indeed,
BDNF treatment reversed neuronal injury caused by FIV
infection in the presence or absence of ddI exposure (P < 0.05). In vivo FIV
infection revealed delays in withdrawal latency to a noxious stimulus, which were exacerbated by ddI treatment. Epidermal density of nerve endings was reduced after FIV
infection (P < 0.05), especially with ddI treatment. Although viral replication in blood was suppressed in ddI-treated animals (P < 0.05), ddI had a limited effect on viral abundance in DRGs of the same animals. ddI decreased mtCOX I expression in DRG neurons of FIV-infected animals (P < 0.05).
BDNF expression was downregulated by ddI in DRG Schwann cells following FIV
infection. Thus, ddI 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.