Neocortical damage during HIV infection

Wiley, Clayton A.; Masliah, Eliezer; Morey, Mitchel; Lemere, Cindy; DeTeresa, Richard; Grafe, Marjorie R.; Hansen, Lawrence A.; Terry, Robert D.

doi:10.1002/ana.410290613

Cited by 430 publications

(165 citation statements)

References 21 publications

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“…Larger neurons were most vulnerable, but neurodegeneration occurred in all lobes. Autopsy studies of AIDS patients with minor cognitive͞motor disorder reveal widespread loss of synapses (20) and reduced dendritic complexity without overt neuronal loss. Other studies of minor cognitive͞motor disorder reveal some cell loss in selected neuronal subpopulations, specifically in MAP-2-immunoreactive and calbindin pyramidal cells (21).…”

Section: Discussionmentioning

confidence: 99%

Thinning of the cerebral cortex visualized in HIV/AIDS reflects CD4 ⁺ T lymphocyte decline

Thompson

Dutton

Hayashi

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

287

273

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HIV͞AIDS infection is the fourth leading cause of death worldwide, and one in every 100 adults aged 15-49 years is HIV-infected. Forty percent of AIDS patients suffer from neurological symptoms, but the selective profile of damage caused by HIV in the brain is not well understood. Here, we report 3D maps revealing how AIDS affects the human cerebral cortex, identifying the most vulnerable regions and where deficits link with cognitive decline and immunesystem suppression. With high-resolution brain MRI scans, we created composite maps of cortical gray-matter thickness in 26 AIDS patients and 14 healthy controls to establish the selective pattern of brain deficits in AIDS. In AIDS, primary sensory, motor, and premotor cortices were 15% thinner. Thinner frontopolar and language cortex correlated with immune system deterioration measured through blood levels of CD4 ؉ T lymphocytes. Prefrontal and parietal tissue loss correlated with cognitive͞motor deficits. T cell depletion and cognitive impairment are, therefore, associated with specific 3D brain-deficit patterns visualized with MRI. These quantitative MRI-based maps reveal that HIV selectively damages the cortex. They provide an approach to gauge the impact of AIDS on the living brain and show that the brain is still vulnerable to infection even when patients are receiving antiretroviral therapy.brain ͉ MRI ͉ disease ͉ T cell ͉ immunity

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Section: Discussionmentioning

confidence: 99%

Thinning of the cerebral cortex visualized in HIV/AIDS reflects CD4 ⁺ T lymphocyte decline

Thompson

Dutton

Hayashi

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

287

273

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“…H uman immunodeficiency virus-1-associated dementia (HAD) 3 is a common neurological complication associated with HIV and is estimated to develop in ϳ20% of infected patients (1). Unlike many viral encephalopathies, neurons are not productively infected by HIV.…”

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confidence: 99%

Signaling Mechanism of HIV-1 gp120 and Virion-Induced IL-1β Release in Primary Human Macrophages

Cheung

Ravyn

Wang

et al. 2008

The Journal of Immunology

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HIV-1 envelope glycoprotein gp120 induces, independently of infection, the release of proinflammatory cytokines, including IL-1β from macrophages, that are implicated in the pathogenesis of HIV-associated dementia. However, the signal transduction pathways involved have not been fully defined. Previously, our laboratory reported that soluble gp120 activates multiple protein kinases in primary human monocyte-derived macrophages, including the Src family kinase Lyn, PI3K, and the focal adhesion-related proline-rich tyrosine kinase Pyk2. In this study we showed that gp120 induces IL-1β release from macrophages in a time- and concentration-dependent manner through binding to the chemokine receptor CCR5 and coupling to Giα protein. Using pharmacological inhibitors and small interfering RNA gene knockdown, we demonstrated that concomitant activation of Lyn, Pyk2, and class IA PI3K are required for gp120-induced IL-1β production. By coimmunoprecipitation and immunofluorescence confocal microscopy, we showed that CCR5 activation by gp120 triggered the assembly of a signaling complex involving endogenous Lyn, PI3K, and Pyk2 and is associated with PI3K and Pyk2 translocation from the cytoplasm to the membrane where they colocalized with Lyn. Finally, we demonstrated that virion-associated gp120 induced similar response, as structurally intact whole virions also triggered IL-1β release and re-localization of PI3K and Pyk2. This study identifies a novel signaling mechanism for HIV-1-induced IL-1β production by primary human macrophages that may be involved in the neuropathogenesis of HIV-associated dementia.

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“…In addition, HIV-1 infection restricted to the production of regulatory gene products in astrocytes has been reported [6,7]. Other prominent pathological findings include widespread activation of microglia, reactive astrocytosis [4], and evidence of neuronal loss and damage to the dendritic arbor [8][9][10][11]. The severity of the clinical dementia correlates best with the presence pathologically of activated microglia, and less well with the number of HIV-1-infected cells [4,[12][13][14].…”

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confidence: 99%

HIV-1-induced neuronal injury in the developing brain

Epstein

Gelbard

1999

Journal of Leukocyte Biology

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HIV-1 infection of the nervous system causes neuronal injury and death, resulting in cognitive, motor, and behavioral dysfunction in both adults and children. In infants a characteristic feature of HIV-1 infection is impaired brain growth resulting in secondary microcephaly with onset between 2 and 4 months of age. This post-natal period of brain development is particularly vulnerable to excitotoxic neuronal injury due to the active synaptogenesis and pruning that takes place at this age associated with over-expression of excitatory amino acid (EAA) receptors. HIV-1 infection of brain microglia and perivascular macrophages results in chronic inflammation manifest pathologically as diffuse microglial activation and reactive astrogliosis. Several inflammatory products of activated microglia, including tumor necrosis factor ␣ (TNF-␣) and platelet-activating factor (PAF) have been shown to act as neuronal toxins. This toxic effect can be antagonized by blocking NMDA (or AMPA) glutamate receptors, suggesting that (weak) excitotoxicity leads to oxidative stress, neuronal injury, and apoptosis. HIV-1 infection and chronic inflammation may also contribute disruption of the blood-brain barrier and could result in further entry into the CNS of toxic viral or cellular products or additional HIV-1-infected cells. We hypothesize that prolonged microglial activation during HIV-1 infection underlies the neuronal injury and impaired brain growth in affected infants. Further investigation of the interaction between HIV-1-infected/activated microglia and developing neurons seems warranted. The current understanding of HIV neuropathogenesis implies that therapeutic strategies should target the sustained immune activation in microglia, attempt to repair the integrity of the blood-brain barrier, and provide ''neuroprotection'' from excitotoxic neuronal injury. J. Leukoc. Biol. 65: 453-457; 1999.

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Neocortical damage during HIV infection

Cited by 430 publications

References 21 publications

Thinning of the cerebral cortex visualized in HIV/AIDS reflects CD4 ⁺ T lymphocyte decline

Thinning of the cerebral cortex visualized in HIV/AIDS reflects CD4 ⁺ T lymphocyte decline

Signaling Mechanism of HIV-1 gp120 and Virion-Induced IL-1β Release in Primary Human Macrophages

HIV-1-induced neuronal injury in the developing brain

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Neocortical damage during HIV infection

Cited by 430 publications

References 21 publications

Thinning of the cerebral cortex visualized in HIV/AIDS reflects CD4 + T lymphocyte decline

Thinning of the cerebral cortex visualized in HIV/AIDS reflects CD4 + T lymphocyte decline

Signaling Mechanism of HIV-1 gp120 and Virion-Induced IL-1β Release in Primary Human Macrophages

HIV-1-induced neuronal injury in the developing brain

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Thinning of the cerebral cortex visualized in HIV/AIDS reflects CD4 ⁺ T lymphocyte decline

Thinning of the cerebral cortex visualized in HIV/AIDS reflects CD4 ⁺ T lymphocyte decline