HIV-1 associated neurocognitive disorders (HAND) remain highly prevalent in the era of effective antiretroviral therapy. HIV-1 infection within CNS system plays a central role in the development of HAND. Drugs of abuse, such as cocaine, have been shown to increase the incidence and exacerbate the severity of HAND by enhancing viral replication. However, the mechanistic links between cocaine and HAND progression remain undefined. Although changes in many neurotransmitter systems may contribute to HAND, the central dopamine (DA) system plays a crucial role in the development of neurocognitive dysfunction in HAND patients and in the control of psychostimulant action of cocaine. The interplay of HIV-1 Tat protein with cocaine augments synaptic DA level and Tat release within dopaminergic brain regions. Long lasting exposure to elevated DA and Tat eventually lead to DA deficit that potentiates severity and accelerates progression of HAND. Antiretroviral agents cannot prevent the production of HIV-1 viral proteins, such as Tat protein, in proviral-containing brain cells. It is unclear how the DA system is altered in HIV-1 positive cocaine abusers. Therefore, there is a pressing need to define the molecular mechanism(s) by which the impaired DA system by HIV-1 infection affects the progression of HAND in concurrent cocaine abusers. Presynaptic DA transporter (DAT), which is critical for neurocognitive function, is a major molecular target for both Tat and cocaine to impact the DA system. In this application, we hypothesize that Tat, via allosteric binding sites in the DAT, potentiates inhibitory effects of cocaine on DA transport, which is the key to DA system dysfunction occurred in HAND patients. Our proposed experiments will investigate how Tat and cocaine interact with the human DAT through their recognition binding sites on human DAT, thereby leading to dysfunction of the DA system. Our strategy encompasses creating a dynamic 3D computational model to predict potential Tat and cocaine binding pocket residues of human DAT, validating these residues via site-directed mutagenesis, and analyzing the consequent functional changes of the Tat and DAT interaction in neuronal cells and primary neurons. The completion of this application will identify molecular targets on the DAT for developing compounds that specifically block Tat binding site(s) in DAT and stabilize physiological dopaminergic tone, which should be beneficial to the preservation of neurocognitive function in patients with HAND in concurrent cocaine abusers.

Public Health Relevance

The prevalence and severity of HIV-1-associated neurocognitive disorders are greatly enhanced (~70%) due to concomitant use of drugs of abuse such as cocaine. This project is to determine the recognition structures of human dopamine transporter interacting with HIV-1 viral proteins and cocaine that are responsible for the impairment of the dopamine system, thereby provide new insights into understanding one important mechanism of HIV-1-associated neurocognitive disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA035714-02
Application #
8690005
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Purohit, Vishnudutt
Project Start
2013-07-01
Project End
2018-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
2
Fiscal Year
2014
Total Cost
$366,215
Indirect Cost
$64,748
Name
University of South Carolina at Columbia
Department
Type
Schools of Pharmacy
DUNS #
041387846
City
Columbia
State
SC
Country
United States
Zip Code
29208
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Quizon, Pamela M; Sun, Wei-Lun; Yuan, Yaxia et al. (2016) Molecular mechanism: the human dopamine transporter histidine 547 regulates basal and HIV-1 Tat protein-inhibited dopamine transport. Sci Rep 6:39048
Sun, Wei-Lun; Quizon, Pamela M; Zhu, Jun (2016) Molecular Mechanism: ERK Signaling, Drug Addiction, and Behavioral Effects. Prog Mol Biol Transl Sci 137:1-40
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Zhu, Jun; Midde, Narasimha M; Gomez, Adrian M et al. (2015) Intra-ventral tegmental area HIV-1 Tat1-86 attenuates nicotine-mediated locomotor sensitization and alters mesocorticolimbic ERK and CREB signaling in rats. Front Microbiol 6:540

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