Abundant expression of HIV Nef and Rev proteins in brain astrocytes in vivo is associated with dementia

Ranki, Annamari; Nyberg, Marcus; Ovod, Vladimir; Haltia, Matti; Elovaara, Irina; Raininko, Raili; Haapasalo, Hannu; Krohn, Kai

doi:10.1097/00002030-199509000-00004

Cited by 276 publications

(178 citation statements)

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“…Because giant macrophages rapidly form upon expression of Nef alone, it indicates that Nef is sufficient to trigger macrophage fusion independently of Env or other viral proteins. Interestingly, among HIV-1 proteins, Nef was the only protein detected in giant macrophages of the brain in AIDS patients (76).…”

Section: Discussionmentioning

confidence: 99%

HIV-1 Nef Triggers Macrophage Fusion in a p61Hck- and Protease-Dependent Manner

Vérollet

Zhang

Cabec

et al. 2010

The Journal of Immunology

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Macrophages are a major target of HIV-1 infection. HIV-1–infected macrophages form multinucleated giant cells (MGCs) using poorly elucidated mechanisms. In this study, we show that MGC formation was reduced when human macrophages were infected with nef-deleted HIV-1. Moreover, expression of Nef, an HIV-1 protein required in several aspects of AIDS, was sufficient to trigger the formation of MGCs in RAW264.7 macrophages. Among Nef molecular determinants, myristoylation was dispensable, whereas the polyproline motif was instrumental for this phenomenon. Nef has been shown to activate hematopoietic cell kinase (Hck), a Src tyrosine kinase specifically expressed in phagocytes, through a well-described polyproline–SH3 interaction. Knockdown approaches showed that Hck is involved in Nef-induced MGC formation. Hck is expressed as two isoforms located in distinct subcellular compartments. Although both isoforms were activated by Nef, only p61Hck mediated the effect of Nef on macrophage fusion. This process was abolished in the presence of a p61Hck kinase-dead mutant or when p61Hck was redirected from the lysosome membrane to the cytosol. Finally, lysosomal proteins including vacuolar adenosine triphosphatase and proteases participated in Nef-induced giant macrophage formation. We conclude that Nef participates in HIV-1–induced MGC formation via a p61Hck- and lysosomal enzyme-dependent pathway. This work identifies for the first time actors of HIV-1–induced macrophage fusion, leading to the formation of MGCs commonly found in several organs of AIDS patients.

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Section: Discussionmentioning

confidence: 99%

HIV-1 Nef Triggers Macrophage Fusion in a p61Hck- and Protease-Dependent Manner

Vérollet

Zhang

Cabec

et al. 2010

The Journal of Immunology

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“…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.…”

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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“…Astrocytes present an abundant CNS target, but the course of infection is generally a long-term latent process. These infected astrocytes lack the productive infection characteristic of MP cells, and express predominantly viral regulatory genes rather than structural genes (132,135). However, any lack of infective robustness does not diminish the importance of astrocyte dysfunction in the dementia process.…”

Section: Impairment Of Astrocytes In Hadmentioning

confidence: 99%

“…In the brain, microglia/macrophage are the primary targets of HIV-1 infection (128), but in vivo infection of astrocytes has been documented in multiple studies (129)(130)(131)(132)(133)(134)(135)(136). Astrocytes present an abundant CNS target, but the course of infection is generally a long-term latent process.…”

Section: Impairment Of Astrocytes In Hadmentioning

confidence: 99%

Potentiation of excitotoxicity in HIV-1-associated Dementia and the significance of glutaminase

Erdmann¹,

Whitney²,

Zheng³

2006

Clinical Neuroscience Research

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HIV-1 Associated Dementia (HAD) is a significant consequence of HIV infection. Although multiple inflammatory factors contribute to this chronic, progressive dementia, excitotoxic damage appears to be an underlying mechanism in the neurodegenerative process. Excitotoxicity is a cumulative effect of multiple processes occurring in the CNS during HAD. The overstimulation of glutamate receptors, an increased vulnerability of neurons, and disrupted astrocyte support each potentiate excitotoxic damage to neurons. Recent evidence suggests that poorly controlled generation of glutamate by phosphate-activated glutaminase may contribute to the neurotoxic state typical of HAD as well as other neurodegenerative disorders. Glutaminase converts glutamine, a widely available substrate throughout the CNS to glutamate. Inflammatory conditions may precipitate unregulated activity of glutaminase, a potentially important mechanism in HAD pathogenesis.

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Abundant expression of HIV Nef and Rev proteins in brain astrocytes in vivo is associated with dementia

Cited by 276 publications

References 0 publications

HIV-1 Nef Triggers Macrophage Fusion in a p61Hck- and Protease-Dependent Manner

HIV-1 Nef Triggers Macrophage Fusion in a p61Hck- and Protease-Dependent Manner

Roles of MCP-1 in development of HIV-dementia

Potentiation of excitotoxicity in HIV-1-associated Dementia and the significance of glutaminase

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