Summary
The recreational use of cocaine can lead to an addiction that increases the risk of acquiring the human
immunodeficiency virus (HIV) through high-risk behaviors such as an increase in unprotected sexual activity,
and a more rapid progression to AIDS. Approximately 33% of the 1.2 million people in the United States (US)
living with HIV use illicit substances, and approximately 1 in 10 new HIV diagnoses are attributed to injection
drug users every year. People living with HIV who take combination antiretroviral therapy (cART) and maintain
viral loads below detectable levels live a near-normal lifespan. However, despite the advances in efficacious
medication, there are still no medications that prevent the viral invasion to the central nervous system (CNS)
solidifying that the risk of developing HIV-1 associated neurocognitive disorders (HAND) has not decreased.
Therefore, to protect chronically infected people from the ravages of HIV-1 infection in the brain, particularly
when combined with substance use disorder (SUD), it is necessary to advance the understanding of the
intersection of HIV-1 and addiction to identify novel therapeutic targets.
Both cocaine and HIV proteins contribute to neuronal damage during disease progression through
dysregulation of glutamate homeostasis in the brain. It has been documented that as high as 19% of astrocytes
in the brains of patients with severe HAND are infected with HIV-1. Nef is one of the earliest expressed viral
proteins in approximately 1% of infected astrocytes. Even without measurable viral replication, Nef could
contribute to continued neuronal degeneration even in patients on cART. Extracellular glutamate is normally
taken up by astrocytes through a glutamate transporter (GLT-1) and exchanged for cysteine through the
cystine/glutamate exchanger. ß -catenin, a dual function protein, regulates the expression of glutamate
transporters preventing neurotoxicity caused by excess NMDA receptor activation in neurons. However, cocaine
downregulates GLT-1 and the cystine/glutamate exchanger. During withdrawal of cocaine exposure, the
AMPA/NMDA ratio increases in the nucleus accumbens (NAc). The NAc is an important brain structure involved
in the development of cocaine addiction. The overall objective is to study the interaction between HIV-1 Nef and
cocaine related to glutamate homeostasis and drug-seeking behavior. The central hypothesis is that combined
cocaine exposure and astrocytic Nef expression will exacerbate glutamate excitation inducing
neurophysiological changes that strengthen synaptic transmission and reinforce the cocaine-seeking behavior.
To address this hypothesis, the team will develop the following two Specific Aims. Aim 1: Determine the impact
of HIV-1 Nef and cocaine on glutamatergic neurotransmission. Aim 2: Determine the impact of HIV-1 Nef on
cocaine-seeking behavior in rats. With the combination of in vivo self-administration, electrophysiology, and
molecular studies using brain tissue, the team will elucidate the role of HIV-1 Nef on cocaine-seeking and
consumption essential to developing new therapies to treat people with HIV and SUD.