The anticancer drug sunitinib promotes autophagyand protects from neurotoxicity in an HIV-1 Tat model of neurodegeneration

Abstract

Despite the success of antiretroviral therapies to control systemic HIV-1 infection, the prevalence of HIV-associated neurocognitive disorders (HAND) has not decreased among aging patients with HIV. Autophagy pathway alterations, triggered by HIV-1 proteins including gp120, Tat, and Nef, might contribute to the neurodegenerative process in aging patients with HAND. Although no treatments are currently available to manage HAND, we have previously shown that Sunitinib, an anti-cancer drug that blocks receptor tyrosine-kinase and cyclin kinase pathways, might be of interest. Studies in cancer models suggest that sunitinib might also modulate autophagy, which is dysregulated in our models of Tat-induced neurotoxicity. We evaluated the efficacy of sunitinib to promote autophagy in the CNS and ameliorate neurodegeneration using LC3-GFP expressing neuronal cells challenged with low concentrations of Tat and using inducible Tat transgenic mice. In neuronal cultures challenged with low levels of Tat, sunitinib increased markers of autophagy such as LC3-II and reduced p62 accumulation in a dose-dependent manner. In vivo, sunitinib treatment restored LC3-II, p62, and Endophilin B1 (EndoB1) levels in doxycycline-induced Tat transgenic mice. Moreover, in these animals sunitinib reduced the hyperactivation of CDK5, tau hyper-phosphorylation and p35 cleavage to p25. Restoration of CDK5 and autophagy were associated with reduced neurodegeneration and behavioral alterations. Alterations in autophagy in the Tat tg mice were associated with reduced levels of a CDK5 substrate, EndoB1, and levels of total EndoB1 were normalized by sunitinib treatment. We conclude that sunitinib might ameliorate Tat-mediated autophagy alterations and may decrease neurodegeneration in aging patients with HAND.

Long-term HIV-1 Tat Expression in the Brain Led to Neurobehavioral, Pathological, and Epigenetic Changes Reminiscent of Accelerated Aging

“…Acute and short-term HIV-1 Tat expression in iTat mice have been linked to astrocytes activation (astrocytosis), compromised neuronal integrity, and neurobehavioral deficits [57,63,72]. To determine the effects of longterm Tat expression on astrocytes activation and neuronal integrity, the brain of iTat mice was harvested at the end of the neurobehavioral studies, the cortex (CORT), striatum (caudate and putamen, CPU), hippocampus (HIP) and cerebellum (CERE) were dissected and analyzed for expression of glial fibrillary acidic protein (GFAP), a marker for astrocytes activation, synaptophysin (SYP), a pre-synaptic marker, and postsynaptic density protein 95 .992] showed no differences between iTat male mice and Wt male mice.…”

Canonical and Non-Canonical Autophagy in HIV-1 Replication Cycle

“…Tat can enter in neurons through endocytosis pathways which are mediated by numerous receptors such as CXCR4, CD26, heparin sulfate proteoglycans or low-density lipoprotein receptor-related proteins [ 121 , 122 , 123 , 124 , 125 ]. In the last few years, an increasing number of studies has found that Tat can modulate autophagy in brain tissues [ 101 , 102 , 103 , 104 , 105 ]. Interestingly, Tat regulates autophagy in a cell-type-dependent manner.…”

“…It has been reported that Tat induces autophagy in human astrocyte cell lines and embryonic rat hippocampal neurons [ 103 , 105 ], and represses this mechanism in primary mouse neuron cells [ 104 ]. More surprisingly, Tat appears to have a dual role in autophagy in neuroblastoma cell lines depending on its concentration [ 101 , 102 ]. Indeed, autophagy is upregulated or downregulated at low or high doses of Tat, respectively.…”

“…Indeed, autophagy is upregulated or downregulated at low or high doses of Tat, respectively. Moreover, while Tat reduces the number of autophagosomes and increases their size at low concentrations [ 102 ], it induces autophagosome accumulation and elicits the formation of misshapen autophagosomes at high concentration [ 101 ]. Interestingly, Fields and collaborators identified an interaction between Tat and lysosome-associated membrane protein 2 (LAMP2) [ 101 ], a lysosomal protein essential for chaperone-mediated autophagy and canonical autophagy [ 126 , 127 ].…”

“…Fields and collaborators have confirmed in vitro results by using an inducible Tat transgenic mouse model. Remarkably, they showed that Tat-mediated induction or repression of autophagy in neurons promote neurodegeneration [ 101 , 102 ]. In addition, they have demonstrated that Tat-mediated autophagy alteration can be reversed by treatment with autophagy inducers, reducing neuronal injury and improving locomotor activity in mice.…”