Histone deacetylase 6 inhibition rescues axonal transport impairments and prevents the neurotoxicity of HIV-1 envelope protein gp120

Abstract

Despite successful antiretroviral drug therapy, a subset of human immunodeficiency virus-1 (HIV)-positive individuals still display synaptodendritic simplifications and functional cognitive impairments referred to as HIV-associated neurocognitive disorders (HANDs). The neurological damage observed in HAND subjects can be experimentally reproduced by the HIV envelope protein gp120. However, the complete mechanism of gp120-mediated neurotoxicity is not entirely understood. Gp120 binds to neuronal microtubules and decreases the level of tubulin acetylation, suggesting that it may impair axonal transport. In this study, we utilized molecular and pharmacological approaches, in addition to microscopy, to examine the relationship between gp120-mediated tubulin deacetylation, axonal transport, and neuronal loss. Using primary rat cortical neurons, we show that gp120 decreases acetylation of tubulin and increases histone deacetylase 6 (HDAC6), a cytoplasmic enzyme that regulates tubulin deacetylation. We also demonstrate that the selective HDAC6 inhibitors tubacin and ACY-1215, which prevented gp120-mediated deacetylation of tubulin, inhibited the ability of gp120 to promote neurite shortening and cell death. We further observed by co-immunoprecipitation and confirmed with mass spectroscopy that exposure of neurons to gp120 decreases the association between tubulin and motor proteins, a well-established consequence of tubulin deacetylation. To assess the physiological consequences of this effect, we examined the axonal transport of brain-derived neurotrophic factor (BDNF). We report that gp120 decreases the velocity of BDNF transport, which was restored to baseline levels when neurons were exposed to HDAC6 inhibitors. Overall, our data suggest that gp120-mediated tubulin deacetylation causes impairment of axonal transport through alterations to the microtubule cytoskeleton.

The Major Capsid Protein, VP1, of the Mouse Polyomavirus Stimulates the Activity of Tubulin Acetyltransferase 1 by Microtubule Stabilization

“…One way to alter microtubule acetylation is to affect HDAC6. The envelope protein gp120 of human immunodeficiency virus 1 (HIV-1) increased the level of HDAC6 in primary rat neurons [53], while influenza A virus reduced the level of HDAC6 in infected cells [54]. We showed that MPyV infection does not affect the mRNA levels of either HDAC6 or αTAT1.…”

“…The stabilization of microtubules and their acetylation favors motor binding, thus enhancing their movement along the microtubules [53,61]. The disruption of microtubules by nocodazole inhibited the release of MPyV from infected cells [50], suggesting that intact and likely stable microtubules are indispensable for the active release of MPyV progeny from infected cells.…”

Direct interaction of HIV gp120 with neuronal CXCR4 and CCR5 receptors induces cofilin-actin rod pathology via a cellular prion protein- and NOX-dependent mechanism

“…Synaptopathy has emerged as a hallmark of HIV-mediated neurotoxicity of HAND in the post-cART era [74] and impairments in neuronal cytoskeleton are highly relevant driven by neurotoxic HIV proteins [93][94][95]. Synaptic dysfunction and dendritic simplification are linked to gp120 neurotoxicity and underlie cognitive impairments observed in HAND yet the mechanisms are poorly understood [12,96,97].…”

HDAC6 in Diseases of Cognition and of Neurons

“…An area of great interest is the treatment of human immunodeficiency virus (HIV)-associated neurocognitive disorders. The neurological damage observed in HIV-positive subjects can be experimentally reproduced by the HIV envelope glycoprotein (gp)120. gp120 binds to neuronal microtubules and decreases the level of tubulin acetylation, with resulting impairment of axonal transport [ 54 , 55 ]. Wenzel et al [ 54 ] showed that the selective HDAC6i tubacin and ACY-1215 prevented gp120-mediated deacetylation of tubulin and inhibited the ability of gp120 to decrease axonal transport.…”

“…The neurological damage observed in HIV-positive subjects can be experimentally reproduced by the HIV envelope glycoprotein (gp)120. gp120 binds to neuronal microtubules and decreases the level of tubulin acetylation, with resulting impairment of axonal transport [ 54 , 55 ]. Wenzel et al [ 54 ] showed that the selective HDAC6i tubacin and ACY-1215 prevented gp120-mediated deacetylation of tubulin and inhibited the ability of gp120 to decrease axonal transport. Indeed, the study showed that gp120 decreases the velocity of BDNF transport, which is restored to baseline levels when neurons are exposed to HDAC6i [ 55 ].…”