This article focuses on the drug cocaine, and its role in facilitating entry of HIV into the CNS and mechanisms of development of neurologic complications in infected individuals. Cocaine is a powerfully addictive central nervous system stimulating drug, which increases the level of neurotransmitter dopamine (DA) in the brain, by blocking the dopamine transporters (DAT) which is critical for DA homeostasis and neurocognitive function. Tat protein of HIV acts as an allosteric modulator of DAT, where as cocaine acts as reuptake inhibitor. When macrophages in the CNS are exposed to DA, their number increases. These macrophages release inflammatory mediators and neurotoxins, causing chronic neuroinflammation. Cocaine abuse during HIV infection enhances the production of platelet monocyte complexes (PMCs), which may cross transendothelial barrier, and result in HIV-associated neurocognitive disorder (HAND). HAND is characterized by neuroinflammation, including astrogliosis, multinucleated giant cells, and neuronal apoptosis that is linked to progressive virus infection and immune deterioration. Cocaine and viral proteins are capable of eliciting signaling transduction pathways in neurons, involving in mitochondrial membrane potential loss, oxidative stress, activation of JNK, p38, and ERK/MAPK pathways, and results in downstream activation of NF-κB that leads to HAND. Tat-induced inflammation provokes permeability of the blood brain barrier (BBB) in the platelet dependent manner, which can potentially be the reason for progression to HAND during HIV infection. A better understanding on the role of cocaine in HIV infection can give a clue in developing novel therapeutic strategies against HIV-1 infection in cocaine using HIV infected population.
Below: Prevalence of cocaine use in 2010 (UNODC). Source: UNODC estimates based on annual report questionnaire data and other official sources. The bound-aries and names shown and the designations used on this map do not imply official endorsement or acceptance by the United Nations. Final boundary between the Republic of Sudan and the Republic of South Sudan has not yet been determined. Dashed lines represent undermined bound-aries. Dotted line represents approximately the line of Control in Jammu and Kashmir agreed upon by India and Pakistan. The final status of Jammu and Kashmir has not yet been agreed upon by the parties. The final boundary between the Republic of Sudan and the Republic of South Sudan has not yet been determined.
Below: The sequence of events that leads to progression toward HIV associated Neurocognitive Disorders (HAND) during cocaine abuse, cocaine + HIV infection and HIV infection alone. Drug abuse (Cocaine) leads to the formation of platelet monocyte complexes (PMCs) which crosses transendothelial barrier and cause neuroinflammation, which possibly results in HAND. Along with the PMCs formation, cocaine also induces neuronal apoptosis by triggering viral products such as Tat and gp120, and potentiates astrocyte toxicity after activation by HIV gp120. gp120 is necessary for the viral infectivity, enhances neurotoxicity via inducible nitric oxide synthesis, and causes cellular oxidative stress which increasingly affects the CNS. It also alters the host glutamate pathway signaling, which interacts with cellular receptor, directing secretion of cytokines and finally affecting the neurons. Cocaine along with gp120 synergistically increases neuronal toxicity by the increase in the activity of caspase-3, increase in reactive oxygen species and loss of mitochondrial potential. Cocaine and gp120 are capable of eliciting signaling transduction pathways in neurons, involving mitochondrial membrane potential loss, oxidative stress, activation of JNK, p38, and ERK/MAPK pathways, and results in downstream activation of NF-κB that leads to HAND.
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By:
1CSIR-Centre for Cellular and Molecular Biology, Hyderabad, India
2College of Medicine, Florida International University, Miami, FL, USA
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