Role of immune activation and cytokine expression in HIV-1-associated neurologic diseases

Yoshioka, Masaru; Bradley, Walter G.; Shapshak, Paul; Nagano, Isao; Stewart, Renee; Xin, Ke Qin; Srivastava, Ashok; Nakamura, Shozo

doi:10.1016/0960-5428(95)00012-q

Cited by 61 publications

(42 citation statements)

References 154 publications

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“…Noncytotoxic defense mechanisms mediated through the production of soluble, inhibitory factors most likely contribute to the control of CNS infections. Although proinflammatory cytokines, such as TNF-␣ and IL-1␤, have been clearly implicated in neuronal damage (15)(16)(17)(18)(19), little is known about the regulatory effect of these cytokines on viral infections of the CNS or whether they possess beneficial, antiviral effects in brain cells. In response to viral infection, cytokines are secreted within the CNS from both activated glial cells and T lymphocyte infiltrates (20).…”

Section: Discussionmentioning

confidence: 99%

Decreased Cytomegalovirus Expression Following Proinflammatory Cytokine Treatment of Primary Human Astrocytes

Cheeran

Gekker

et al. 2000

The Journal of Immunology

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Understanding the influence of immune effector mechanisms on CMV infection of the CNS may facilitate the development of immunotherapies for viral encephalitis. Using cultures of highly purified, fully permissive primary human astrocytes, proinflammatory cytokines, but not antiinflammatory cytokines or β-chemokines, were found to inhibit CMV expression, DNA synthesis, and replication. Treatment with certain proinflammatory cytokines 24 h before CMV infection markedly suppressed viral expression in astrocytes. TNF-α, IL-1β, and IFN-γ all inhibited CMV expression (70 ± 4.2%, 65 ± 3.4%, and 82 ± 3.6% inhibition of viral expression, respectively, n = 5). In contrast, no viral suppression was observed following IL-6 treatment. Suppressive activity was dependent on the addition of cytokines before CMV infection. Cytokine pretreatment did not affect CMV entry into primary astrocytes, and the observed cytokine-induced suppressive activity was not affected by the NO synthase inhibitor NG-monomethyl-l-arginine (NGMA). Instead, the suppressive effect appeared to be mediated through a mechanism involving inhibition of CMV major immediate early promoter activity. These results support the hypothesis that proinflammatory cytokines possess anti-CMV activity in brain cells and may lead to new interventions for CMV encephalitis based upon immunotherapy.

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Section: Discussionmentioning

confidence: 99%

Decreased Cytomegalovirus Expression Following Proinflammatory Cytokine Treatment of Primary Human Astrocytes

Cheeran

Gekker

et al. 2000

The Journal of Immunology

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“…Further, in¯ammatory responses in the CNS have also been linked to speci®c types of neurological disease, such as autoimmune processes in multiple sclerosis (Benveniste, 1992), AIDS dementia (Adamson et al, 1996;Talley et al, 1995;Yoshioka et al, 1995), or other CNS viral infections (Lieberman et al, 1989). Astrocytes and other glial cells during the in¯ammatory response in the CNS may in¯uence the balance between host protection and neurotoxicity.…”

Section: Discussionmentioning

confidence: 99%

Astrocytes as targets for Venezuelan equine encephalitis virus infection

et al. 1999

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Venezuelan equine encephalitis virus (VEE) produces an acute infection in humans and induces a well-characterized cytopathic effect in neurons of the central nervous system (CNS). However, little is known about the role of glial cells in response to VEE infection of the CNS. Our results demonstrate that VEE is capable of a productive infection in primary astrocyte cultures and that this infection is cytotoxic. Further, there were signi®cant differences in the growth kinetics comparing virulent and attenuated strains of VEE. Additionally, VEE infection of astrocyte cultures induced gene expression of two neuro-immune modulators, tumor necrosis factor-alpha (TNF-a) and inducible nitric oxide synthase (iNOS). Assays for TNF-a protein and nitric oxide (NO) demonstrated high levels of TNF-a protein and low levels of NO in response to VEE infection of astrocytes. These observations suggest an important role of astrocytes in this virus-induced encephalitis, and that interactions between astrocytes, other glial cells, and neurons may be important in VEE pathogenesis. Such interactions, which could impact neuronal survival, may include loss of functional changes in astrocytes or, alternatively, their production of neurotoxic molecules.

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“…However, increasing evidence suggests that inflammation is actively involved in the pathogenesis of HAD (7)(8)(9)(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).…”

Section: Introductionmentioning

confidence: 99%

Roles of MCP-1 in development of HIV-dementia

Dhillon¹

2008

Front Biosci

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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...

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Role of immune activation and cytokine expression in HIV-1-associated neurologic diseases

Cited by 61 publications

References 154 publications

Decreased Cytomegalovirus Expression Following Proinflammatory Cytokine Treatment of Primary Human Astrocytes

Decreased Cytomegalovirus Expression Following Proinflammatory Cytokine Treatment of Primary Human Astrocytes

Astrocytes as targets for Venezuelan equine encephalitis virus infection

Roles of MCP-1 in development of HIV-dementia

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