Tenofovir disoproxil fumarate induces peripheral neuropathy and alters inflammation and mitochondrial biogenesis in the brains of mice

Abstract

Mounting evidence suggests that antiretroviral therapy (ART) drugs may contribute to the prevalence of HIV-associated neurological dysfunction. The HIV envelope glycoprotein (gp120) is neurotoxic and has been linked to alterations in mitochondrial function and increased inflammatory gene expression, which are common neuropathological findings in HIV+ cases on ART with neurological disorders. Tenofovir disproxil fumarate (TDF) has been shown to affect neurogenesis in brains of mice and mitochondria in neurons. In this study, we hypothesized that TDF contributes to neurotoxicity by modulating mitochondrial biogenesis and inflammatory pathways. TDF administered to wild-type (wt) and GFAP-gp120 transgenic (tg) mice caused peripheral neuropathy, as indicated by nerve conduction slowing and thermal hyperalgesia. Conversely TDF protected gp120-tg mice from cognitive dysfunction. In the brains of wt and gp120-tg mice, TDF decreased expression of mitochondrial transcription factor A (TFAM). However, double immunolabelling revealed that TFAM was reduced in neurons and increased in astroglia in the hippocampi of TDF-treated wt and gp120-tg mice. TDF also increased expression of GFAP and decreased expression of IBA1 in the wt and gp120-tg mice. TDF increased tumor necrosis factor (TNF) α in wt mice. However, TDF reduced interleukin (IL) 1β and TNFα mRNA in gp120-tg mouse brains. Primary human astroglia were exposed to increasing doses of TDF for 24 hours and then analyzed for mitochondrial alterations and inflammatory gene expression. In astroglia, TDF caused a dose-dependent increase in oxygen consumption rate, extracellular acidification rate and spare respiratory capacity, changes consistent with increased metabolism. TDF also reduced IL-1β-mediated increases in IL-1β and TNFα mRNA. These data demonstrate that TDF causes peripheral neuropathy in mice and alterations in inflammatory signaling and mitochondrial activity in the brain.

Transcriptomic analysis of brain tissues identifies a role for CCAAT enhancer binding protein β in HIV-associated neurocognitive disorder

“…However, recent studies suggest that HIV infection of astrocytes is reduced or non-existent in brains of PWH on ART [68]. Nevertheless, the findings presented here are consistent with our recent report showing that tenofovir disproxil fumarate activates astroglia and increases inflammatory cytokines [69]. Moreover, HIV and inflammatory cytokines increase C/EBPβ expression by astrocytes [11].…”

Transcriptomic analysis of brain tissues identifies a role for CCAAT enhancer binding protein β in HIV-associated neurocognitive disorders

“…However, recent studies suggest that HIV infection of astrocytes is reduced or non-existent in brains of PWH on ART [69]. Nevertheless, the findings presented here are consistent with our recent report showing that tenofovir disproxil fumarate activates astroglia and increases inflammatory cytokines [70]. Moreover, HIV and inflammatory cytokines increase C/EBPb expression by astrocytes [11].…”

Predictors of worsening neuropathy and neuropathic pain after 12 years in people with HIV

“…30,31 Studies using animal models exposed to tenofovir disoproxil fumarate support a role for ART in DSP. 32 However, more work is needed to understand how DSP manifests despite reduced viral loads.…”

“…At the same time, ART has been associated with the development of DSP symptoms in some individuals despite reducing viral load 30,31 . Studies using animal models exposed to tenofovir disoproxil fumarate support a role for ART in DSP 32 . However, more work is needed to understand how DSP manifests despite reduced viral loads.…”