The National NeuroAIDS Tissue Consortium Brain Gene Array: Two Types of HIV-Associated Neurocognitive Impairment

Gelman, Benjamin B.; Chen, Tiansheng; Lisinicchia, Joshua G.; Soukup, Vicki M.; Carmical, J. Russ; Starkey, Jonathan M.; Masliah, Eliezer; Commins, Deborah; Brandt, Dianne; Grant, Igor; Singer, Elyse J.; Levine, Andrew J.; Miller, Jeremy A.; Winkler, Jessica M.; Fox, Howard S.; Luxon, Bruce A.

doi:10.1371/journal.pone.0046178

Cited by 146 publications

(206 citation statements)

References 96 publications

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“…Immunoreactivity was detected using 3,3=-diaminobenzidine tetrachloride (brown) and/or 5-bromo-4-chloroindolylphosphate (blue) (32). All human brain specimens were collected with consent (19).…”

Section: Quantitative Reverse Transcription-pcr (Rt-pcr) Analysismentioning

confidence: 99%

“…The decedents used in this work were from the National NeuroAIDS Tissue Consortium (NNTC) (19). The use of autopsied brain tissues is part of ongoing research (Pro00002291) approved by the University of Alberta Human Research Ethics Board (Biomedical).…”

Section: Figmentioning

confidence: 99%

“…Nonetheless, a substantial proportion of HIV/AIDS patients receiving HAART display HAND (ϳ20%), with a worsened overall survival (18). HIV/AIDS patients receiving HAART at the time of death display both provirus and viral RNA together with ongoing neuroinflammation (19).…”

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confidence: 99%

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Neuroinflammation-Induced Interactions between Protease-Activated Receptor 1 and Proprotein Convertases in HIV-Associated Neurocognitive Disorder

Kim

Zekas

Lodge

et al. 2015

Molecular and Cellular Biology

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eThe proprotein convertases (PCs) furin, PC5, PACE4, and PC7 cleave secretory proteins after basic residues, including the HIV envelope glycoprotein (gp160) and Vpr. We evaluated the abundance of PC mRNAs in postmortem brains of individuals exhibiting HIV-associated neurocognitive disorder (HAND), likely driven by neuroinflammation and neurotoxic HIV proteins (e.g., envelope and Vpr). Concomitant with increased inflammation-related gene expression (interleukin-1␤ [IL-1␤]), the mRNA levels of the above PCs are significantly increased, together with those of the proteinase-activated receptor 1 (PAR1), an inflammation-associated receptor that is cleaved by thrombin at ProArg 41 2 (where the down arrow indicates the cleavage location), and potentially by PCs at Arg 41 XXXXArg 46 2. The latter motif in PAR1, but not its R46A mutant, drives its interactions with PCs. Indeed, PAR1 upregulation leads to the inhibition of membrane-bound furin, PC5B, and PC7 and inhibits gp160 processing and HIV infectivity. Additionally, a proximity ligation assay revealed that furin and PC7 interact with PAR1. Reciprocally, increased furin expression reduces the plasma membrane abundance of PAR1 by trapping it in the trans-Golgi network. Furthermore, soluble PC5A/PACE4 can target/disarm cell surface PAR1 through cleavage at Arg 46 2. PACE4/PC5A decreased calcium mobilization induced by thrombin stimulation. Our data reveal a new PC-PAR1-interaction pathway, which offsets the effects of HIVinduced neuroinflammation, viral infection, and potentially the development of HAND.

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Section: Quantitative Reverse Transcription-pcr (Rt-pcr) Analysismentioning

confidence: 99%

Section: Figmentioning

confidence: 99%

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Neuroinflammation-Induced Interactions between Protease-Activated Receptor 1 and Proprotein Convertases in HIV-Associated Neurocognitive Disorder

Kim

Zekas

Lodge

et al. 2015

Molecular and Cellular Biology

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“…The National NeuroAIDS Tissue Consortium (NNTC) performed a brain gene expression array to elucidate pathophysiology of HIV-1-associated neurocognitive disorders (Gelman et al, 2012). Gelman et al analyzed the global gene profiles of neocortex, white matter, and neostriatum among HIV-1 infected subjects with no substantial neurocognitive impairment (NCI), with substantial NCI without HIV-1 encephalitis (HIVE); and those with substantial NCI and HIVE in comparison with uninfected controls.…”

Section: Complement In Aids-related Neurodegenerative Diseases Such Amentioning

confidence: 99%

Complement and HIV-I infection/HIV-associated neurocognitive disorders

et al. 2014

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The various neurological complications associated with HIV-1 infection, specifically HIV-associated neurocognitive disorders (HAND) persist as a major public health burden worldwide. Despite the widespread use of anti-retroviral therapy, the prevalence of HAND is significantly high. HAND results from the direct effects of an HIV-1 infection as well as secondary effects of HIV-1-induced immune reaction and inflammatory response. Complement, a critical mediator of innate and acquired immunity, plays important roles in defeating many viral infections by the formation of a lytic pore or indirectly by opsonization and recruitment of phagocytes. While the role of complement in the pathogenesis of HIV-1 infection and HAND has been previously recognized for over fifteen years, it has been largely underestimated thus far. Complement can be activated through HIV-1 envelope proteins, mannose binding lectins (MBL) and anti-HIV-1 antibodies. Complement not only fights against HIV-1 infection but also enhances HIV-1 infection. Also, HIV-1 can hijack complement regulators such as CD59 and CD55 and can utilize these regulators and factor H to escape from complement attack. Normally, complement levels in brain are much lower than plasma levels and there is no or little complement deposition in brain cells. Interestingly, local production and deposition of complement are dramatically increased in HIV-1-infected brain, indicating that complement may contribute to the pathogenesis of HAND. Here, we review the current understanding of the role of complement in HIV-1 infection and HAND as well as potential therapeutic approaches targeting to the complement system for the treatment and eradications of HIV-1 infection.

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“…A gene expression array demonstrated that there may be two forms of cognitive impairment that occur in the present era of antiretroviral therapy driven by differing pathophysiologies [76]. “Type I” impairment is characterized by HIV encephalitis and high CNS viral loads which persist in some individuals despite cART.…”

Section: Introductionmentioning

confidence: 99%

Monocytes Mediate HIV Neuropathogenesis: Mechanisms that Contribute to HIV Associated Neurocognitive Disorders

Williams¹,

Veenstra²,

Gaskill³

et al. 2014

CHR

131

129

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HIV infected people are living longer due to the success of combined antiretroviral therapy (cART). However, greater than 40-70% of HIV infected individuals develop HIV associated neurocognitive disorders (HAND) that continues to be a major public health issue. While cART reduces peripheral virus, it does not limit the low level, chronic neuroinflammation that is ongoing during the neuropathogenesis of HIV. Monocyte transmigration across the blood brain barrier (BBB), specifically that of the mature CD14+CD16+ population that is highly susceptible to HIV infection, is critical to the establishment of HAND as these cells bring virus into the brain and mediate the neuroinflammation that persists, even if at low levels, despite antiretroviral therapy. CD14+CD16+ monocytes preferentially migrate into the CNS early during peripheral HIV infection in response to chemotactic signals, including those from CCL2 and CXCL12. Once within the brain, monocytes differentiate into macrophages and elaborate inflammatory mediators. Monocytes/macrophages constitute a viral reservoir within the CNS and these latently infected cells may perpetuate the neuropathogenesis of HIV. This review will discuss mechanisms that mediate transmigration of CD14+CD16+ monocytes across the BBB in the context of HIV infection, the contribution of these cells to the neuropathogenesis of HIV, and potential monocyte/macrophage biomarkers to identify HAND and monitor its progression.

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The National NeuroAIDS Tissue Consortium Brain Gene Array: Two Types of HIV-Associated Neurocognitive Impairment

Cited by 146 publications

References 96 publications

Neuroinflammation-Induced Interactions between Protease-Activated Receptor 1 and Proprotein Convertases in HIV-Associated Neurocognitive Disorder

Neuroinflammation-Induced Interactions between Protease-Activated Receptor 1 and Proprotein Convertases in HIV-Associated Neurocognitive Disorder

Complement and HIV-I infection/HIV-associated neurocognitive disorders

Monocytes Mediate HIV Neuropathogenesis: Mechanisms that Contribute to HIV Associated Neurocognitive Disorders

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