Sunday, May 4, 2025
5/4/2025
The Role of HIV Proteins in Psychostimulant Abuse - Project Summary: The use of amphetamine (AMPH) and its derivatives (e.g. methAMPH) has been linked to human immunodeficiency virus (HIV) transmission1, as HIV can spread through heightened unprotected sexual activity2, 3 that is associated with AMPH use disorder (AUD) 5, 6. For these and other reasons, AMPH dependence and HIV infection have been termed a double epidemic7. In this bidirectional relationship, the role played by AUD in synergizing HIV dependent neurodegeneration is well documented. For example, AUD exacerbates HIV impairments of central dopamine (DA) neurotransmission8-10. Furthermore, the HIV trans-activator of transcription regulatory protein Tat1-86 (Tat) and AMPH act in concert to impair striatal DA function11. Conversely, HIV and HIV proteins have been shown to enhance specific AMPH-induced behaviors. In rodents, expression of HIV proteins such as Tat, gp120, etc. enhance AMPH escalation12. Consistently, in humans, HIV infection increases AMPH frequency of use, frequency and duration of binging, as well as amount1, 13-17. This is important since the DSM-5 criteria for addiction includes a progressive intensification in drug use (i.e. escalation). To date, no examples exist of verified mechanisms or molecular descriptions of how HIV/HIV viral proteins alter AMPH molecular actions and/or behavioral expressions. This is the focus of this application. AMPH behavioral expressions (e.g. AUD) stem, at least in part, from their ability to reverse the function of the DA transporter (DAT), causing non-vesicular DA release, here defined as NVDR, resulting in an increase in extracellular DA levels4, 18. DAT is a plasma membrane protein that clears extracellular DA by its active transport into presynaptic terminals19. To gain a deeper understanding of NVDR, we provided the first evidence that specific domains of human DAT (hDAT) engage in direct association with the plasma membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP2). These domains include the distal hDAT N-terminus (hDAT NT), and the hDAT intracellular loop 4 (IL4)4, 18, which contain basic residues that establish a network of electrostatic interactions with the anionic heads of PIP2. These interactions are essential for AMPH-induced hDAT NT phosphorylation, an event required for the interaction of hDAT NT with IL4 and for AMPH to promote NVDR and specific behaviors, including “sexual motivation”4, 18, 20. Tat is an unique HIV secreted protein, as it binds the anionic PIP2 with high affinity through its basic domains21-23. Consistent with Tat high affinity for PIP2, we demonstrated that Tat alters the electrostatic interaction of hDAT with PIP2 and, as a consequence, impairs NVDR. Of note is that escalation of drug intake is associated with blunted drug-evoked DA release, especially in psychostimulant use models24, 25. Thus, it is possible that Tat, by blunting AMPH-induced DA release (i.e. NVDR), promotes an increase in AMPH use1, 12-17. Here, by integrating a broad range of experimental approaches, we will test our mechanistic hypothesis that the molecular, functional and behavioral roles of Tat in AUD stem, at least in part, from their ability to regulate NVDR, a process dictated by its interactions with PIP2.
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