Alterations in the Levels of Vesicular Trafficking Proteins Involved in HIV Replication in the Brains and CSF of Patients with HIV-associated Neurocognitive Disorders

Fields, Jerel Adam; Dumaop, Wilmar; Adame, Anthony; Ellis, Ronald J.; Letendre, Scott; Grant, Igor; Masliah, Eliezer

doi:10.1007/s11481-013-9511-3

Cited by 12 publications

(14 citation statements)

References 34 publications

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“…Numerous studies have addressed potential HIV-associated CSF biomarkers that may be used alone or in combination to either predict CNS disease severity or to predict the progression of HIV CNS disease [16-20]. Similarly, many studies have assessed changes in hpTau levels in CSF as a biomarker in AD, and more recently in HIV [21].…”

Section: Introductionmentioning

confidence: 99%

Changes in PINCH levels in the CSF of HIV+ individuals correlate with hpTau and CD4 count

et al. 2014

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Several studies report associations between the PINCH (particularly interesting new cysteine histidine-rich) protein and HIV-associated CNS disease. PINCH is detected in the CSF of HIV patients and changes in levels during disease may be indicative of changes in disease status over time. PINCH binds hyperphosphorylated Tau (hpTau) in the brain and CSF, but little is known about the relevance of these interactions to HIV CNS disease. In this study, PINCH and hpTau levels were assessed in three separate CSF samples collected longitudinally from 20 HIV+ participants before and after initiating antiretroviral therapy, or before and after a change in the current regimen. The intervals were approximately 1 (T2), and 3-7 (T3) months from the initial visit (baseline, T1). Correlational analyses were conducted for CSF levels of PINCH and hpTau and other variables including blood CD4+ T-cell count, plasma and CSF viral burden, CSF neopterin, white blood cell (WBC) count, and antiretroviral CNS penetration-effectiveness (CPE). Values for PINCH and hpTau were determined for each patient by calculating the fold changes between the second (T2) and third measurements (T3) from the baseline measurement (T1). Statistical analyses showed that the fold-change in CSF PINCH protein from T1 to T2 were significantly higher in participants with CD4 counts >200 cells/mm3 at T2 compared to those with CD4 counts <200 cells/mm3 at T2. This trend persisted irrespective of plasma or CSF viral burden or anti-retroviral therapy CPE scores. The fold-changes in PINCH levels between T1 and T2, and T1 and T3 were highly correlated to the fold changes in hpTau at T2/T1 and T3/T1 (correlation co-efficient = 0.69, p-value < 0.001, correlation co-efficient = 0.83, p-value <0.0001, respectively). In conclusion, in these HIV participants, changes in CSF levels of PINCH appear to correlate with changes in blood CD4 count and with changes in CSF hpTau levels, but not with plasma or CSF viral burden, neopterin, or WBC, or with anti-retroviral regimen CPE.

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Section: Introductionmentioning

confidence: 99%

Changes in PINCH levels in the CSF of HIV+ individuals correlate with hpTau and CD4 count

et al. 2014

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“…Recently, differences in the levels of autophagy markers between young and old HIV patients with encephalitis have been reported, with the former patients displaying an increase in BECLIN-1, CATHEPSIN D and LC3, whilst these proteins are reduced in the latter group compared to agematched HIV patients without encephalitis [80]. Of note, these differences correlate with the severity of neurodegenerative pathology.…”

Section: Autophagy Alterations In the Central Nervous System During Hmentioning

confidence: 99%

“…It is important to note that some of the effects of TAT on autophagy may be indirect, as it is also able to interfere with the endo-lysosomal compartment, by increasing luminal pH and compromising membrane integrity [84]. A recent detailed study of the effect of TAT on autophagy showed that treatments both in vitro and in GFAP-TAT transgenic mice induce accumulation of abnormal neuronal autophagosomes, suggesting that TAT alters the fusion of autophagosomes with lysosomes [80]. It is interesting that TAT was found in association with the lysosomal protein LAMP2A.…”

Section: Autophagy Alterations In the Central Nervous System During Hmentioning

confidence: 99%

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Role of autophagy in HIV infection and pathogenesis

et al. 2017

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The aim of autophagy is to re‐establish homeostasis in response to a variety of stress conditions. By forming double‐membrane vesicles, autophagy engulfs damaged or superfluous cytoplasmic material and recycles degradation products for new synthesis or energy production. Of note, the same mechanism is used to capture pathogens and has important implications in both innate and adaptive immunity. To establish a chronic infection, pathogens have therefore evolved multiple mechanisms to evade autophagy‐mediated degradation. HIV infection represents one of the best characterized systems in which autophagy is disarmed by a virus using multiple strategies to prevent the sequestration and degradation of its proteins and to establish a chronic infection. HIV alters autophagy at various stages of the process in both infected and bystander cells. In particular, the HIV proteins TAT, NEF and ENV are involved in this regulation by either blocking or stimulating autophagy through direct interaction with autophagy proteins and/or modulation of the mTOR pathway. Although the roles of autophagy during HIV infection are multiple and vary amongst the different cell types, several lines of evidence point to a potential beneficial effect of stimulating autophagy‐mediated lysosomal degradation to potentiate the immune response to HIV. Characterization of the molecular mechanisms regulating selective autophagy is expected to be valuable for developing new drugs able to specifically enhance the anti‐HIV response.

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“…Moreover, previous studies have shown that HIV-1 proteins might trigger neurodegeneration by interfering with clearance pathways such as macroautophagy (Alirezaei et al , 2008a; Alirezaei et al , 2008b; Zhou et al , 2011), a pathway necessary for recycling proteins or defective and older intracellular organelles (Cuervo, 2004). These alterations in autophagy in HIV-1 patients and transgenic (tg) mice are exacerbated with age (Fields et al , 2013a). Moreover, HIV-1 Tat (trans-activator of transcription) could either activate or suppress, depending on the conditions, autophagy function in glial cells (Bruno et al , 2014), macrophages (Wang et al , 2011) and bystander monocytes (Schenk et al , 2011), and Tat triggers neurodegeneration by disrupting endolysosomal functioning (Hui et al , 2012).…”

Section: Introductionmentioning

confidence: 99%

The anticancer drug sunitinib promotes autophagyand protects from neurotoxicity in an HIV-1 Tat model of neurodegeneration

et al. 2017

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Despite the success of antiretroviral therapies to control systemic HIV-1 infection, the prevalence of HIV-associated neurocognitive disorders (HAND) has not decreased among aging patients with HIV. Autophagy pathway alterations, triggered by HIV-1 proteins including gp120, Tat, and Nef, might contribute to the neurodegenerative process in aging patients with HAND. Although no treatments are currently available to manage HAND, we have previously shown that Sunitinib, an anti-cancer drug that blocks receptor tyrosine-kinase and cyclin kinase pathways, might be of interest. Studies in cancer models suggest that sunitinib might also modulate autophagy, which is dysregulated in our models of Tat-induced neurotoxicity. We evaluated the efficacy of sunitinib to promote autophagy in the CNS and ameliorate neurodegeneration using LC3-GFP expressing neuronal cells challenged with low concentrations of Tat and using inducible Tat transgenic mice. In neuronal cultures challenged with low levels of Tat, sunitinib increased markers of autophagy such as LC3-II and reduced p62 accumulation in a dose-dependent manner. In vivo, sunitinib treatment restored LC3-II, p62, and Endophilin B1 (EndoB1) levels in doxycycline-induced Tat transgenic mice. Moreover, in these animals sunitinib reduced the hyperactivation of CDK5, tau hyper-phosphorylation and p35 cleavage to p25. Restoration of CDK5 and autophagy were associated with reduced neurodegeneration and behavioral alterations. Alterations in autophagy in the Tat tg mice were associated with reduced levels of a CDK5 substrate, EndoB1, and levels of total EndoB1 were normalized by sunitinib treatment. We conclude that sunitinib might ameliorate Tat-mediated autophagy alterations and may decrease neurodegeneration in aging patients with HAND.

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Alterations in the Levels of Vesicular Trafficking Proteins Involved in HIV Replication in the Brains and CSF of Patients with HIV-associated Neurocognitive Disorders

Cited by 12 publications

References 34 publications

Changes in PINCH levels in the CSF of HIV+ individuals correlate with hpTau and CD4 count

Changes in PINCH levels in the CSF of HIV+ individuals correlate with hpTau and CD4 count

Role of autophagy in HIV infection and pathogenesis

The anticancer drug sunitinib promotes autophagyand protects from neurotoxicity in an HIV-1 Tat model of neurodegeneration

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