Neurodegeneration and Ageing in the HAART Era

Brew, Bruce J.; Crowe, Suzanne; Landay, Alan; Cysique, Lucette A.; Guillemin, Gilles J.

doi:10.1007/s11481-008-9143-1

Cited by 190 publications

(159 citation statements)

References 108 publications

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“…32 The increased cellular iron levels observed in our studies may be a consequence of virus attempting to establish a favorable environment for its own replication. As tissue iron accumulation is seen in many HIV-associated diseases, including neurodegeneration and diastolic cardiac dysfunction, [33][34][35][36][37] it is tempting to speculate that altered cellular iron homeostasis secondary to HIV infection may, at least partially, contribute to the organ damage associated with HIV infection.…”

Section: Relationship Among Iron Hiv and Art 309mentioning

confidence: 99%

Short Communication: High Cellular Iron Levels Are Associated with Increased HIV Infection and Replication

Chang

Bayeva²,

Taiwo

et al. 2015

AIDS Research and Human Retroviruses

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Section: Relationship Among Iron Hiv and Art 309mentioning

confidence: 99%

Short Communication: High Cellular Iron Levels Are Associated with Increased HIV Infection and Replication

Chang

Bayeva²,

Taiwo

et al. 2015

AIDS Research and Human Retroviruses

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“…HIV-1 infection of macrophages leads to long-lived survival and low levels of constitutive virus production, generating macrophage viral reservoirs, 1 which contribute to HIV-1 associated neurocognitive diseases (HAND). 2 HIV-1 viral protein R (Vpr) mediates many processes that promote HIV-1 infection, allows evasion of the immune system, and facilitates persistence in the host cells. 3 Vpr is known to promote viral replication in monocytes and differentiated macrophages.…”

Section: Introductionmentioning

confidence: 99%

Glutamate metabolism in HIV-1 infected macrophages: Role of HIV-1 Vpr

et al. 2016

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HIV-1 infected macrophages play a significant role in the neuropathogenesis of AIDS. HIV-1 viral protein R (Vpr) not only facilitates HIV-1 infection but also contribute to long-lived persistence in macrophages. Our previous studies using SILAC-based proteomic analysis showed that the expression of critical metabolic enzymes in the glycolytic pathway and tricarboxylic acid (TCA) cycle were altered in response to Vpr expression in macrophages. We hypothesized that Vpr-induced modulation of glycolysis and TCA cycle regulates glutamate metabolism and release in HIV-1 infected macrophages.We assessed the amount of specific metabolites induced by Vpr and HIV-1 in macrophages at the intracellular and extracellular level in a time-dependent manner utilizing multiple reaction monitoring (MRM) targeted metabolomics. In addition, stable isotope-labeled glucose and an MRM targeted metabolomics assay were used to evaluate the de novo synthesis and release of glutamate in Vpr overexpressing macrophages and HIV-1 infected macrophages, throughout the metabolic flux of glycolytic pathway and TCA cycle activation.The metabolic flux studies demonstrated an increase in glucose uptake, glutamate release and accumulation of a-ketoglutarate (a-KG) and glutamine in the extracellular milieu in Vpr expressing and HIV-1 infected macrophages. Interestingly, glutamate pools and other intracellular intermediates (glucose-6-phosphate (G6P), fructose-6-phosphate (F6P), citrate, malate, a-KG, and glutamine) showed a decreased trend except for fumarate, in contrast to the glutamine accumulation observed in the extracellular space in Vpr overexpressing macrophages.Our studies demonstrate that dysregulation of mitochondrial glutamate metabolism induced by Vpr in HIV-1 infected macrophages commonly seen, may contribute to neurodegeneration via excitotoxic mechanisms in the context of NeuroAIDS.

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“…We recently observed significant relationships between clinical variables and both cortical and subcortical volumes among people infected with HIV, with disease history (nadir CD4, duration of infection) being most strongly associated with cortical volumes . This raises the concern that brain pathology incurred during the clinical history may increase vulnerability to neurodegeneration, with cortical changes analogous to premature aging (Brew et al, 2009;Valcour et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Cerebral metabolite abnormalities in human immunodeficiency virus are associated with cortical and subcortical volumes

Cohen

Harezlak

Gongvatana

et al. 2010

Journal of NeuroVirology

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Cerebral metabolite disturbances occur among human immunodeficiency virus (HIV)-infected people, and are thought to reflect neuropathology, including proinflammatory processes, and neuronal loss. HIV-associated cortical atrophy continues to occur, though its basis is not well understood, and the relationship of cerebral metabolic disturbance to structural brain abnormalities in HIV has not been well delineated. We hypothesized that metabolite disturbances would be associated with reduced cortical and subcortical volumes. Cerebral volumes were measured in 67 HIV-infected people, including 10 people with mild dementia (acquired immunodeficiency syndrome [AIDS] Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript cerebral metabolites N-acetylaspartate (NAA), myo-inositol (MI), choline-containing compounds (Cho), glutamate/glutamine (Glx), and creatine (Cr) from three brain regions (frontal gray matter, frontal white matter, basal ganglia). Analyses were conducted to examine the associations between MRS and cerebral volumetric measures using both absolute and relative metabolite concentrations. NAA in the mid-frontal gray matter was most consistently associated with cortical (global, frontal, and parietal), ventricular, and caudate volumes based on analysis of absolute metabolite levels, whereas temporal lobe volume was associated with basal ganglia NAA and Glx, and Cho concentrations in the frontal cortex and basal ganglia. Hippocampal volume was associated with frontal white matter NAA, whereas thalamic volume was associated with both frontal white matter NAA and basal ganglia Glx. Analyses of relative metabolite concentrations (referenced to Cr) yielded weaker effects, although more metabolites were retained as significant predictors in the models than the analysis of absolute concentrations. These findings demonstrate that reduced cortical and subcortical volumes, which have been previously found to be linked to HIV status and history, are also strongly associated with the degree of cerebral metabolite disturbance observed via MRS. Reduced cortical and hippocampal volumes were most strongly associated with decreased NAA, though reduced Glx also tended to be associated with reduced cortical and subcortical volumes (caudate and thalamus) as well, suggesting both neuronal and glial disturbances. Interestingly, metabolite-volumetric relationships were not limited to the cortical region from which MRS was measured, possibly reflecting shared pathophysiological processes. The relationships between Cho and volumetric measures suggest a complicated relationship possibly related to the effects of inflammatory processes on brain volume. The findings demonstrate the relationship between MRI-derived measures of cerebral metabolite disturbances and structural brain integrity, which has implication in understanding HIV-associated neuropathological mechanisms.

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Neurodegeneration and Ageing in the HAART Era

Cited by 190 publications

References 108 publications

Short Communication: High Cellular Iron Levels Are Associated with Increased HIV Infection and Replication

Short Communication: High Cellular Iron Levels Are Associated with Increased HIV Infection and Replication

Glutamate metabolism in HIV-1 infected macrophages: Role of HIV-1 Vpr

Cerebral metabolite abnormalities in human immunodeficiency virus are associated with cortical and subcortical volumes

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