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Interactive effects of cocaine on HIV infection: implication in HIV-associated neurocognitive disorder and neuroAIDS.

Dahal S, Chitti SV, Nair MP, Saxena SK - Front Microbiol (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: CSIR-Centre for Cellular and Molecular Biology , Hyderabad, India.

ABSTRACT
Substantial epidemiological studies suggest that not only, being one of the reasons for the transmission of the human immunodeficiency virus (HIV), but drug abuse also serves its role in determining the disease progression and severity among the HIV infected population. 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.

No MeSH data available.


Related in: MedlinePlus

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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Figure 2: 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.

Mentions: Neurologic complications may occur up to 40% of AIDS patients and nearly 25% of HIV infected persons who have not clinically progressed to AIDS (Carvour et al., 2015). During the later stages of the disease, HIV-1 infected patients suffer from a wide range of neurological and neurocognitive disorders collectively known as HIV-associated neurocognitive disorder (HAND; Atluri et al., 2014). It is characterized by neuroinflammation, including astrogliosis, multinucleated giant cells, and neuronal apoptosis that is linked to progressive virus infection and immune deterioration (Saiyed et al., 2011). Neuronal apoptosis, a result of neuronal dysfunction, stands as one of the features of HIV-associated dementia which is induced by diverse cellular and viral factors, inclusive of viral proteins Tat and gp120. Drugs of abuse act synergistically with HIV proteins to potentiate HIV related neurotoxicity (Yuan et al., 2015) and affect many functions associated with the synaptic plasticity. Introduction of the anti-retroviral therapy (ART) has decreased the cases of HAND. However, drug abuse is playing a crucial role in the prevalence of HAND in the HIV infected individuals. Cocaine use serves as a potential factor for the progression to the HAND in the HIV infected persons. One proposed mechanism is via formation of platelet monocyte complexes (PMCs). Interaction between monocytes and activated platelets leads to the formation of PMCs, and these monocytes has enhanced capability to cross trans-endothelial barrier and cause neuroinflammation, which possibly results in HAND (Tiwari et al., 2013). 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 (Yang et al., 2010). gp120 is necessary for the viral infectivity, enhances neurotoxicity via inducible nitric oxide synthesis, and causes cellular oxidative stress which increasingly affects the CNS (Figure 2). It also alters the host glutamate pathway signaling, which interacts with cellular receptor, directing secretion of cytokines and finally affecting the neurons (Samikkannu et al., 2011). Cocaine along with gp120 has been shown to synergistically increase neuronal toxicity. This has been defined by the increase in the activity of caspase-3, increase in reactive oxygen species and loss of mitochondrial potential. Studies have also suggested that cocaine and gp120 alone 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 (Yao et al., 2009). In vitro studies have shown that neuronal toxicity has been found to be associated with increased cathepsin B secretion in MDM with HIV infection along with cocaine treatment (Zenón et al., 2014).


Interactive effects of cocaine on HIV infection: implication in HIV-associated neurocognitive disorder and neuroAIDS.

Dahal S, Chitti SV, Nair MP, Saxena SK - Front Microbiol (2015)

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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Figure 2: 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.
Mentions: Neurologic complications may occur up to 40% of AIDS patients and nearly 25% of HIV infected persons who have not clinically progressed to AIDS (Carvour et al., 2015). During the later stages of the disease, HIV-1 infected patients suffer from a wide range of neurological and neurocognitive disorders collectively known as HIV-associated neurocognitive disorder (HAND; Atluri et al., 2014). It is characterized by neuroinflammation, including astrogliosis, multinucleated giant cells, and neuronal apoptosis that is linked to progressive virus infection and immune deterioration (Saiyed et al., 2011). Neuronal apoptosis, a result of neuronal dysfunction, stands as one of the features of HIV-associated dementia which is induced by diverse cellular and viral factors, inclusive of viral proteins Tat and gp120. Drugs of abuse act synergistically with HIV proteins to potentiate HIV related neurotoxicity (Yuan et al., 2015) and affect many functions associated with the synaptic plasticity. Introduction of the anti-retroviral therapy (ART) has decreased the cases of HAND. However, drug abuse is playing a crucial role in the prevalence of HAND in the HIV infected individuals. Cocaine use serves as a potential factor for the progression to the HAND in the HIV infected persons. One proposed mechanism is via formation of platelet monocyte complexes (PMCs). Interaction between monocytes and activated platelets leads to the formation of PMCs, and these monocytes has enhanced capability to cross trans-endothelial barrier and cause neuroinflammation, which possibly results in HAND (Tiwari et al., 2013). 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 (Yang et al., 2010). gp120 is necessary for the viral infectivity, enhances neurotoxicity via inducible nitric oxide synthesis, and causes cellular oxidative stress which increasingly affects the CNS (Figure 2). It also alters the host glutamate pathway signaling, which interacts with cellular receptor, directing secretion of cytokines and finally affecting the neurons (Samikkannu et al., 2011). Cocaine along with gp120 has been shown to synergistically increase neuronal toxicity. This has been defined by the increase in the activity of caspase-3, increase in reactive oxygen species and loss of mitochondrial potential. Studies have also suggested that cocaine and gp120 alone 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 (Yao et al., 2009). In vitro studies have shown that neuronal toxicity has been found to be associated with increased cathepsin B secretion in MDM with HIV infection along with cocaine treatment (Zenón et al., 2014).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: CSIR-Centre for Cellular and Molecular Biology , Hyderabad, India.

ABSTRACT
Substantial epidemiological studies suggest that not only, being one of the reasons for the transmission of the human immunodeficiency virus (HIV), but drug abuse also serves its role in determining the disease progression and severity among the HIV infected population. 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.

No MeSH data available.


Related in: MedlinePlus