Drug use is the second leading cause of acquiring HIV (Human Immunodeficiency Virus). It is well-known, that using illicit drugs such as marijuana, opiates, amphetamines, and cocaine, increases susceptibility to becoming infected with HIV due to high risk behavior associated with drug use, such as, unprotected sex, particularly in exchange for drugs or money, and non compliance to anti-retroviral treatment. However, the likelihood of acquiring HIV/AIDS is increased by cocaine use in both heterosexual and homosexual women and men, regardless of intravenous (IV) drug use. Even when compared to IV drug users of other drugs, such as opiates, the incidence of HIV is greater in cocaine addicts. This indicates that increased susceptibility to HIV can’t be explained by this factor alone. Additionally, there is an association between cocaine abuse and rapid conversion of HIV infections to AIDS.
Cofactor in HIV pathogenesis
Chimera mice were used to investigate the effect of cocaine on HIV pathogenicity. Specially breed mice, humanized to express a functional human immune system, were infected with HIV in the presence or absence of cocaine. Cocaine co-exposure led to the acceleration of HIV infection, a decrease in CD4+ cells, and a significant spike in circulating viral load. (Hybrid human-mouse model was used because normal mouse cells do not become infected with HIV, and exposing human test subjects to HIV and cocaine would be unethical and illegal).
Cocaine is a significant cofactor for HIV infection and transmission. Inhaling smoking, snorting, or injecting cocaine is associated with a 2 to 3 fold increase in HIV transmission and acceleration towards AIDS. It has been shown to exacerbate disease severity in frequent users, but for reasons beyond risky behavior and treatment non-compliance. There as several reasons why cocaine may contribute to HIV infection, transmission, and progression. These reasons are related to cocaine’s ability to function as an immunomodulator. It alters the normal function of the immune system, by directly or indirectly acting on white blood cells, particularly CD4+ T-cells.
CD4+ T-cells are the main target for HIV-1 infection within the body, and the site of viral replication. Cocaine may negatively impact the immune system by altering expression of these inflammatory immune cells, inducing oxidative damage, and cell death. Cocaine also promotes HIV gene expression and replication.
Cocaine’s Mechanism of Action
Infection of Immune Cells
Cocaine inhibits the reuptake of catecholamines, such as, dopamine and norepinephrine, in the Central nervous system and the Peripheral nervous system. Cocaine acts through the dopamine receptors in the brain and the Sigma-1 receptor on peripheral blood monocytes. These receptors are involved in regulating immune function.
Cocaine’s action through the sigma-1 receptor plays a role in HIV progression. When researchers blocked the receptor using a sigma-1 agonist drug, the effect of cocaine enhanced HIV replication was abolished. Evidence that cocaine’s natural action facilitates HIV pathogenicity.
HIV entry into the cell is facilitated by the binding of viral glycoproteins to the CD4 receptor and chemokine receptor, known as, CCR5 and CXCR4., respectively. Cocaine induced extracellular norepinephrine causes an increase in the expression of co-receptors CCR5 and CXCR4. Viral proteins fuse with the receptors on the cell membrane, and cause the release of the viral complex into the cytoplasm of the cell. Once the virus enters the cell, the presence of norepinephrine also enhances its transcription and replication.
Increased Immune Cell Activation
Cocaine exposure can alter the normal function of the myeloid cells in the immune system, such as monoctyes, macrophages, and helper T cells. With regular use, cocaine disrupts the homeostasis between Type I (Th1) and Type II (Th2) helper T-cells. When activated these cells trigger an immune response by releasing pro-inflammatory proteins called cytokines and chemokines, that regulate cellular responses necessary to clear pathogens during infection. Cocaine shifts the balance between Th1 and Th2 cellular response, in favor of Th2. Th1 is responsible for a cell mediated immunological response, while Th2 confers a humoral immune response. A strong cell-mediated response is associated with the ability to control HIV, while predominance of TH2 humoral response results in progression to AIDS.
Cocaine alters chemokines and results in a shift in Th1 and Th2 equilibrium. By blocking the reuptake of catecholamines, cocaine allows for a build up of extracellular norepinephrine which suppresses Type I responses. Th1 and Th2 counterbalance each other, and a shift favoring Th2 cytokine and chemokine expression is present in persons that develop AIDS. Type 2 CD4+ T-cells response results in an increased cellular susceptibility to HIV infection and transmission.
Additionally, the unchecked inflammatory response created by an inbalance between Th1/Th2 response leads to apoptosis of Type1 helper T-cells. This is due to T cell exhaustion, from prolonged activation, which causes a loss of function, loss of proliferation, and inability to secrete cytokines and chemokines.
Synergy between Cocaine & HIV: Decreased T-cell Count
Ultimately cocaine suppresses the immune system, by decreasing the levels of CD4+ T cells. When compared to non-users, HIV negative cocaine users have been found to have less of these cells. It has been suggested that cocaine works synergistically with HIV to cause immunodeficiency.
Aside from indirect cell death through activation and increased infection of immune by the virus, cocaine is directly cytotoxic to immune cells. It induces the formation of toxic reactive oxygen species (ROS), causing mitochondrial membrane disruption. Mitochondria are the power source within cells, depolarization of the mitochondrial membrane results in apoptosis. CCR5 and CXCR4 also play a role is this cell death, mediating the binding of HIV glycoproteins to the cell surface.
Signs & Symptoms of Cocaine Use in HIV infection
Declining CD4+ T cell counts trigger the invasion of CD8+ T cells. Th1 CD4+ cells protect against intracellular pathogens, thereby controlling the virus within infected cells. The virus hijacks these cells, causing them to produce more virus, before causing cell death. When they die, circulating viral load increases, promoting Th2 CD4+ cell proliferation. TH2 CD4+ cells are responsible for clearing extracellular pathogens, and for triggering B cells to produce antibodies. In addition, cytotoxic cells, also known as, CD8+ T cells increase. Cytotoxic cells are essential in controlling viremia, and invade during acute increases in viral load, as a last-ditch effort to control progression towards AIDS.
Cocaine has been shown to cause a decrease in CD4+ T-cell count, an increase in viral load, and an increase in CD8+ T-cells. Increased CD8+ T-cells, is indicative of anti-retroviral treatment failure, and is associated with accelerated progression of HIV disease.
Cocaine & CNS Pathogenesis
HIV can be found in the Central Nervous System (CNS) just days after infection. HIV weakens the shield between the blood and the brain, known, as the blood brain barrier (BBB), allowing the virus to cross into the brain inside of infected monocyte cells. Once inside the brain monocytes mature into macrophages and produce more HIV, thus spreading the infection to glial cells in the brain (microglia, astrocytes, oligodendroctyes). Microglia, resident macrophage in the brain, are the main targets of HIV. Cocaine increases the permeability of the BBB, enhancing HIV induced neuroinvasion of inflammatory immune cells.
In addition, cocaine disrupts the normal function of glial cells, which are non-neuronal cells within the CNS. They are the harbingers of HIV infection, and serve as reservoirs for the virus. Infection with HIV in these cells can result in Neuro-acquired Immunodeficiency Syndrome (NueroAIDS).
HIV in the brain causes HIV-associated Neurocognitive Disorders (HAND). The signs and symptoms of HAND include: cognitive dysfunction, behavioral changes, motor deficits, dementia, and encephalitis. Antiretroviral treatment has reduced the prevalence of the most severe forms of HAND, encephalitis and dementia — they are now rare. However, an estimated 40 to 70 percent of people infected with HIV still suffer from the milder forms of HAND. Despite the use of antiviral therapy, the occurrence of HAND in drug users is prevalent, and can be found in persons whose viral loads are suppressed.
Cocaine promotes the replication of HIV in the CNS. This is evidenced by a more rapid onset of NueroAIDS in HIV-infected cocaine users than in HIV- infected nonusers. Cocaine users also experience greater disease severity.
Cocaine is detrimental to the immune system, as such, it increases the risk of acquiring HIV and the ability of HIV infection in drug-users to develop into AIDS. Cocaine decreases cell-mediated immunity, thereby increasing susceptibility for viral infections, as cocaine use has also been correlated with increased incidence of Hepatitis C infection. At the cellular level, cocaine enhances transmission of HIV, by increasing HIV gene expression and replication, through the upregulation of chemokine receptors which allow entry of the virus into the cell. It thereby modulates the immune system, driving inflammation, inducing oxidative stress, and decreasing beneficial T-cell counts through apoptosis. One of the pathological repercussions of these events is neurodegeneration. Cocaine use heightens the development of HIV/AIDS related neurocognitive disorders, by enhancing viral replication, increasing cellular levels of viral proteins, and inducing neuro-inflammation.
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