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.