HIV-associated sensory polyneuropathy and neuronal injury are associated with miRNA–455-3p induction

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Abstract

Symptomatic distal sensory polyneuropathy (sDSP) is common and debilitating in people with HIV/AIDS, leading to neuropathic pain, although the condition’s cause is unknown. To investigate biomarkers and associated pathogenic mechanisms for sDSP, we examined plasma miRNA profiles in HIV/AIDS patients with sDSP or without sDSP in 2 independent cohorts together with assessing related pathogenic effects. Several miRNAs were found to be increased in the Discovery Cohort (sDSP, n = 29; non-DSP, n = 40) by array analyses and were increased in patients with sDSP compared with patients without sDSP. miR–455-3p displayed a 12-fold median increase in the sDSP group, which was confirmed by machine learning analyses and verified by reverse transcription PCR. In the Validation Cohort (sDSP n = 16, non-DSP n = 20, healthy controls n = 15), significant upregulation of miR–455-3p was also observed in the sDSP group. Bioinformatics revealed that miR–455-3p targeted multiple host genes implicated in peripheral nerve maintenance, including nerve growth factor (NGF) and related genes. Transfection of cultured human dorsal root ganglia with miR–455-3p showed a concentration-dependent reduction in neuronal β-III tubulin expression. Human neurons transfected with miR–455-3p demonstrated reduced neurite outgrowth and NGF expression that was reversed by anti–miR–455-3p antagomir cotreatment. miR–455-3p represents a potential biomarker for HIV-associated sDSP and might also exert pathogenic effects leading to sDSP.

Authors

Eugene L. Asahchop, William G. Branton, Anand Krishnan, Patricia A. Chen, Dong Yang, Linglong Kong, Douglas W. Zochodne, Bruce J. Brew, M. John Gill, Christopher Power