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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.
Highlights
Mounting evidence suggests that antiretroviral therapy (ART) drugs may contribute to the prevalence of HIV-associated neurological dysfunction
Indices of peripheral neuropathy are induced by Tenofovir disproxil fumarate but cognitive performance is protected
This study provides the first evidence for the ART drug, Tenofovir disproxil fumarate (TDF), affecting peripheral nerve function and central nervous system (CNS) inflammation and mitochondrial biogenesis in an in vivo setting
Summary
Mounting evidence suggests that antiretroviral therapy (ART) drugs may contribute to the prevalence of HIV-associated neurological dysfunction. TDF 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. Studies have shown that low-level HIV protein expression may persist in PWH on ART13,14, but mounting evidence suggest that ART drugs may underlie some of the neurological dysfunction[15,16,17,18,19,20]. Initial studies determined that NRTI drugs altered the function of human mtDNA polymerase γ and damaged mtDNA21,24 Reductions in metabolites such as acylcarnitine in the brain suggested that mitochondrial dysfunction may persist in people on ART25,26. Increased astroglial TFAM may be due to activation by inflammatory cytokines, though the precise mechanism of this shift in HAND brains is not well understood[37]
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