Mechanisms of HIV-1 Tat Neurotoxicity via CDK5 Translocation and Hyper-Activation: Role in HIV-Associated Neurocognitive Disorders

Abstract

The advent of more effective antiretroviral therapies has reduced the frequency of HIV dementia, however the prevalence of milder HIV associated neurocognitive disorders [HAND] is actually rising. Neurodegenerative mechanisms in HAND might include toxicity by secreted HIV-1 proteins such as Tat, gp120 and Nef that could activate neuro-inflammatory pathways, block autophagy, promote excitotoxicity, oxidative stress, mitochondrial dysfunction and dysregulation of signaling pathways. Recent studies have shown that Tat could interfere with several signal transduction mechanisms involved in cytoskeletal regulation, cell survival and cell cycle re-entry. Among them, Tat has been shown to hyper-activate cyclin-dependent kinase [CDK] 5, a member of the Ser/Thr CDKs involved in cell migration, angiogenesis, neurogenesis and synaptic plasticity. CDK5 is activated by binding to its regulatory subunit, p35 or p39. For this manuscript we review evidence showing that Tat, via calcium dysregulation, promotes calpain-1 cleavage of p35 to p25, which in turn hyper-activates CDK5 resulting in abnormal phosphorylation of downstream targets such as Tau, collapsin response mediator protein-2 [CRMP2], doublecortin [DCX] and MEF2. We also present new data showing that Tat interferes with the trafficking of CDK5 between the nucleus and cytoplasm. This results in prolonged presence of CDK5 in the cytoplasm leading to accumulation of aberrantly phosphorylated cytoplasmic targets [e.g.: Tau, CRMP2, DCX] that impair neuronal function and eventually lead to cell death. Novel therapeutic approaches with compounds that block Tat mediated hyper-activation of CDK5 might be of value in the management of HAND.

Caffeine Blocks HIV-1 Tat-Induced Amyloid Beta Production and Tau Phosphorylation

“…Consistent with previous findings by others and us that HIV-1 Tat increases neuronal Aβ generation (Rempel and Pulliam, 2005; Giunta et al, 2009; Aksenov et al, 2010; Chen et al, 2013) and tau phosphorylation (Giunta et al, 2009; Fields et al, 2015), we demonstrated in SH-SY5Y human neuroblastoma cells over-expressing wild-type AβPP that HIV-1 Tat treatment significantly increased levels of secreted Aβ 1–40 and Aβ 1–42 (Figure 1A). The HIV-1 Tat concentration used here is consistent with the Tat levels (>4000 pg/ml) measured in CSF of infected individuals regardless of viral load (Johnson et al, 2013).…”

“…High concentrations of HIV-1 Tat levels (>4000 pg/ml) were observed in CSF of HIV infected individuals regardless of viral load (Johnson et al, 2013). HIV-1 has been shown to increase neuronal Aβ generation (Rempel and Pulliam, 2005; Giunta et al, 2009; Aksenov et al, 2010) and tau phosphorylation (Giunta et al, 2009; Fields et al, 2015). HIV-1 Tat enters neurons rapidly by receptor-mediated endocytosis with the assistance of low-density lipoprotein receptor-related protein (LRP-1) (Liu et al, 2000; Vendeville et al, 2004; King et al, 2006; Deshmane et al, 2011).…”

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

“…Next we measured the levels of EndoB1, also referred as BIF1, (Figure 2A, D) since this molecule has been shown to regulate autophagy via interactions with the UV radiation resistance-associated gene (UVRAG)/Beclin1 complex (Wong et al , 2011). Moreover, EndoB1 is a substrate of CDK5 (Wong et al , 2011), which is hyper-activated by Tat (Fields et al , 2015b; Lee et al , 2013), and as we have shown, sunitinib modulates CDK5 activation (Wrasidlo et al , 2014). In vehicle-treated cells, challenge with Tat resulted in reduced EndoB1 compared to non-Tat-challenged cells (Figure 2A, D).…”

“…Among other pathways, Tat-mediated neurodegeneration has been associated with hyper-activation of CDK5 and accumulation of increased Tau phosphorylation (Fields et al , 2015b; Lee et al , 2013). Consistent with this notion and similar to the biochemical findings in Figure 5, we found that compared to non-tg mice (treated with vehicle or sunitinib), vehicle treated Tat tg mice displayed increased CDK5, p35 and pTau immunoreactive in the cortex (Figure 7A-D).…”

“…The main differences are that the gp120 studies focused on the effects of sunitinib regulating CDK5 and substrates such as Tau phospho-epitopes and CRMP2 in a model mimicking the acute effects of HIV-1 infection using a high concentration of HIV-1 proteins for a short time period. (Fields et al , 2015b; Wrasidlo et al , 2014), In the present study we investigated the protective effects of sunitinib via induction of autophagy and substrates such as EndoB1 using a chronic, low-level Tat neurotoxicity mouse model, which mimics older individuals with HIV-1 whom have been on cART for a long time,…”