Roles of MCP-1 in development of HIV-dementia

Abstract

The encephalopathy caused by HIV, known clinically as HIV-associated dementia (HAD) and pathologically as HIV encephalitis (HIVE), results from intense infiltration of mononuclear cells, productive replication of the virus in monocyte-derived macrophages/microglia, abortive replication in astrocytes and activation of macrophages/microglia and astrocytes leading to neuronal degeneration in the brains of infected persons. Recent findings have suggested that development of HAD is based more on the activation process than on direct evidence of virus replication in the brain. Since HAD is based on the encephalitic process, major studies have been directed to the mechanisms regulating the inflammatory process. Monocyte chemoattractant protein 1, MCP-1, is a chemokine that is implicated in this process and also in the development of activation in the brain. In this review, we have attempted to identify mechanisms that induce expression of MCP-1 in the brain and the role that it plays in recruitment of mononuclear cells from blood to brain and in the activation processes of inflammatory and neural cells that lead to development of degenerative changes in the neuronal population. KeywordsHIV-1; HAD; Neurons; Astrocytes; Macrophages; Blood Brain Barrier; Review INTRODUCTIONIn recent years the incidence of HIV-associated dementia (HAD) as an AIDS-defining illness has actually increased (1-4) with more prevalence of minor cognitive/motor disorder than frank dementia (5,6). Approximately 20% of AIDS patients develop neurological deficits severe enough to be diagnosed as dementia (1) and therefore, HAD still remains a significant independent risk factor for AIDS-related death.The CNS has been thought to be an immunologically privileged organ. However, increasing evidence suggests that inflammation is actively involved in the pathogenesis of HAD (7-10). HIV encephalitis (HIVE), the pathologic correlate of HAD is characterized by the presence of unusually large numbers of HIV-infected macrophages in the brain, formation of multinucleated giant cells, activation of astrocytes and microglia, all accompanied by cytokine/ chemokine dysregulation, and neuronal degeneration (7,(11)(12)(13)(14). The highly productive infection in macrophages in the brain is also accompanied by an abortive infection in astrocytes [15][16][17][18]. Although the primary cell types infected by HIV-1 in the brain are macrophages/ microglia, and to a lesser extent, astrocytes but not neurons, the low numbers of infected cells in the brain do not correlate with the severity of encephalopathy. Rather, the severity of HAD/ HIVE correlates with the presence of activated glial cells rather than with the presence and amount of HIV-infected cells in the brain and the current thinking about the disease is that CNS injury is mainly caused by the release of neurotoxic factors by immune-activated glial cells (7,13). The combined infection of macrophages/microglia and astrocytes leads to excessive production of viral gene products and host immune response fac...

CCR5 Knockout Prevents Neuronal Injury and Behavioral Impairment Induced in a Transgenic Mouse Model by a CXCR4-Using HIV-1 Glycoprotein 120

“…Some of the up-regulated factors had previously been implicated in HIV neuropathogenesis, such as CCL2, CCL5 and CXCL10 (46–52). However, in this study we investigated the potential role of LCN2, a 25 kDa soluble acute phase protein (39), which had not previously been implicated in HIV-associated brain injury.…”

Chemokines and Viral Infections of the CNS

“…CCL2 levels are significantly increased during HIV-1-induced encephalitis (HIVE) and the chemokine accumulates in the CSF and brains of patients with HAD and HIVE, as well as in macaques with Simian immunodeficiency virus (SIV)-induced encephalitis (SIVE) (Mankowski et al, 2004;Monteiro de Almeida et al, 2005;Monteiro de Almeida et al, 2006). The expression of CCL2 in the CNS is associated with enhanced progression of HIV encephalitis, due to its ability to recruit monocytes and lymphocytes (Dhillon et al, 2008). In addition to CCL2, CXCL10 also can attract inflammatory cells and has been detected in the CSF of HIV-1-infected patients (Kolb et al, 1999).…”

Neuroimmune Pharmacology of Neurodegenerative and Mental Diseases

“…Thus, a significant proportion of HIV-1-infected individuals are drug users, and their poor neuropathological performance could potentially be connected with the neurotoxic and immunomodulating effects caused by the drugs used (Anthony and Bell 2008;Kraft-Terry et al 2009;Nath et al 2008). For instance, cocaine has been shown to accelerate neuronal apoptosis induced by HIV-1 proteins (Aksenov et al 2006) and to facilitate the recruitment of infected mononuclear cells into the CNS through the upregulation of monocyte chemoattractant protein-1 secretion by brain endothelial cells (Dhillon et al 2008;Zhang et al 1998). In HIV-1-infected individuals, methamphetamine administration was reported to increase loss of interneurons in the frontal cortex, which has been correlated with memory deficits (Chana et al 2006) and has been shown to increase the rate of neuropsychological impairment (Rippeth et al 2004).…”