Jun Zhu, MD, PhD

Dr Zhu’s main research is to determine the molecular mechanisms of HIV-1 infection-induced neurological disorders in HIV-1 patients with concurrent substance abuse. About one-half of HIV-1-positive individuals suffer from HIV-associated neurocognitive disorders (HAND), which dramatically affects memory, learning, decision-making, planning and overall quality of life. Drugs of abuse, such as cocaine and methamphetamine, have been shown to exacerbate the severity of HAND. HAND is associated with HIV-1 viral proteins, which are present in the brain of HIV-1-infected patients. For a long time, the idea of the HIV virus crossing the blood-brain barrier was not even considered, but it’s now clear that HIV-1 viral proteins are released in the brain where they disrupt normal brain functions. HIV-1 transactivator of transcription (Tat) protein, an HIV-1 regulatory protein, is thought to inhibit neuronal communication by acting directly on the human dopamine transporter (hDAT), norepinephrine transporter (hNET) and serotonin transporter (hSERT), presynaptic membrane proteins in the brain responsible for pumping the dopamine/norepinephrine/serotonin back into the cytosol and terminating the monoamine signaling during neurotransmission. The Zhu lab uses cutting edge computational modeling, pharmacological, genetic, and behavioral techniques to identify the mechanisms by which Tat perturbs the regulatory network of DAT, NET and SERT that normally sustains concentrative the neurotransmitters and potentiates cocaine’s effects on DAT, NET and SERT, resulting in monoamine dysregulation-linked neuropsychiatric dysfunction prominently featured in HAND. 

 Current ongoing research projects in Zhu’s laboratory: 

1. 1. Molecular mechanisms: Dysregulation of monoamine transporters by HIV-1 Tat and cocaine: Our published work has demonstrated that HIV-1 Tat protein dysregulates monoamine transmission by its allosteric interaction with monoamine transporters (DAT, NET and SERT) in inducible Tat transgenic (iTat-tg) mice, suggesting that Tat protein dysregulates monoamine homeostasis via inhibition of monoamine transporters. This may potentially increase vulnerability to developing impulsivity, cognitive depression, and cocaine abuse in HIV-infected individuals. Ongoing studies will (1) through computational modeling and experimental validation, identify the recognition binding pockets on human SERT for Tat, cocaine, allosteric modulator and explore the potential interactions with Tat and cocaine, (2) characterize the pathophysiological role of the SERT in Tat- and cocaine-dysregulated monoaminergic transmission, and (3) perform the proof-of-concept studies using a pharmacological approach with chemical probes to establish their potential for therapeutic application in treating impulsivity and depression. 
   2. Effects of HIV-1 Tat protein and methamphetamine on VMAT2-mediated dopamine transmission in the context of neuroHIV and drug abuse: DAT transports the extracellular dopamine into cytosolic space of the synaptic terminals, whereas the vesicular monoamine transporter2 (VMAT2) transports the cytosolic DA into synaptic vesicles, whereby both DA transporter and VMAT2 are critical for normal DA homeostasis. We have demonstrated that Tat protein increases extracellular DA concentration by directly inhibiting DAT, however, the cellular mechanisms underlying Tat-induced inhibition of VMAT2-mediated DA release/uptake remains unexplored. Ongoing studies will (1) through computational modeling and experimental validation, identify the recognition binding pockets on human VMAT2 for Tat, METH, or novel VMAT2 inhibitors and explore the potential interactions of the inhibitors with Tat and METH, (2) characterize the pathophysiological roles of VMAT2 in Tat- and METH-dysregulated DA system, and (3) perform proof-of-concept studies using pharmacological and genetic approaches as biological probes to establish their potential for therapeutic application in HAND in concurrent METH users.
   3. Allosteric Modulators of Dopamine Transporter as Therapeutic Agents for NeuroAIDS: This is a drug development project. Our published work has demonstrated that in vivo expression of Tat protein dysregulates monoamine transmission by its allosteric interaction with DAT, NET and SERT in inducible Tat transgenic (iTat-tg) mice. We have identified SRI- 32743, a novel allosteric modulator, which attenuates Tat-inhibited DA transport via DAT, NET or SERT and alleviates Tat-potentiated cognitive impairments and cocaine reward in iTat-tg mice. Through further structure activity relationship studies, we identified four analogs of SRI-32743 with improved solubility and metabolic stability. The four analogs display partial inhibitory capability for monoamine transporters and attenuate Tat-induced inhibition of DAT-mediated DA uptake through an allosteric mechanism. Ongoing studies will (1) design and synthesize novel allosteric ligands in recognition for Tat and cocaine binding sites on monoamine transporters as potential probes for in vivo pharmacological studies; (2) characterize the in vitro pharmacological profile of the compounds to identify optimized probe molecules; and (3) determine the therapeutic role of novel allosteric modulators in alleviation of Tat-mediated cognitive deficits and rewarding effects of cocaine in iTat-tg and EcoHIV mice.