HIV and antiretroviral therapy in the brain: neuronal injury and repair

Ellis, Ronald J.; Langford, Dianne; Masliah, Eliezer

doi:10.1038/nrn2040

Cited by 466 publications

(410 citation statements)

References 144 publications

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“…For example, it has been shown that dephosphorylation and inhibition of the IRBIT released with inositol 1,4,5-trisphosphate leads to Ca 2ϩ release from the ER and causes aberrant neuronal regulation (49), whereas the stress-associated endoplasmic reticulum protein 1 (SERP1) has been shown to stabilize ER membrane proteins during stress (50) and protects unfolded target proteins against degradation during ER stress. Similarly, maintaining the proper axon diameter size by NEFM is essential for the conduction of nerve impulses (51). Furthermore, distribution of the mitochondria inside the axon is essential to control ATP levels and cell-to-cell communication.…”

Section: Identification Of Genes Regulated By Tat In Neurons-mentioning

confidence: 99%

HIV-1 Tat Protein Promotes Neuronal Dysfunction through Disruption of MicroRNAs

Chang

Mukerjee

Bagashev

et al. 2011

Journal of Biological Chemistry

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Over the last decade, small noncoding RNA molecules such as microRNAs (miRNAs) have emerged as critical regulators in the expression and function of eukaryotic genomes. It has been suggested that viral infections and neurological disease outcome may also be shaped by the influence of small RNAs. This has prompted us to suggest that HIV infection alters the endogenous miRNA expression patterns, thereby contributing to neuronal deregulation and AIDS dementia. Therefore, using primary cultures and neuronal cell lines, we examined the impact of a viral protein (HIV-1 Tat) on the expression of miRNAs due to its characteristic features such as release from the infected cells and taken up by noninfected cells. Using microRNA array assay, we demonstrated that Tat deregulates the levels of several miRNAs. Interestingly, miR-34a was among the most highly induced miRNAs in Tat-treated neurons. Tat also decreases the levels of miR-34a target genes such as CREB protein as shown by real time PCR. The effect of Tat was neutralized in the presence of anti-miR-34a. Using in situ hybridization assay, we found that the levels of miR-34a increase in Tat transgenic mice when compared with the parental mice. Therefore, we conclude that deregulation of neuronal functions by HIV-1 Tat protein is miRNA-dependent.

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Section: Identification Of Genes Regulated By Tat In Neurons-mentioning

confidence: 99%

HIV-1 Tat Protein Promotes Neuronal Dysfunction through Disruption of MicroRNAs

Chang

Mukerjee

Bagashev

et al. 2011

Journal of Biological Chemistry

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“…For example, dephosphorylation and inhibition of the IP 3 R-binding protein (IRBIT) released with IP 3 leads to Ca 2ϩ release from the ER and causes aberrant neuronal regulation (32), while the stress-associated endoplasmic reticulum protein 1 (SERP1) has been shown to stabilize ER membrane proteins during stress (33) and protects unfolded target proteins against degradation during ER stress. Similarly, maintaining the proper axon diameter size is essential for the conduction of nerve impulses (34). Further, distribution of the mitochondria inside the axon is essential to control ATP levels and cell-to-cell communication.…”

Section: Detection Of Vpr In Neural Cells Inmentioning

confidence: 99%

Deregulation of microRNAs by HIV-1 Vpr Protein Leads to the Development of Neurocognitive Disorders

Mukerjee

Chang

Valle

et al. 2011

Journal of Biological Chemistry

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Studies have shown that HIV-infected patients develop neurocognitive disorders characterized by neuronal dysfunction.The lack of productive infection of neurons by HIV suggests that viral and cellular proteins, with neurotoxic activities, released from HIV-1-infected target cells can cause this neuronal deregulation. The viral protein R (Vpr), a protein encoded by HIV-1, has been shown to alter the expression of various important cytokines and inflammatory proteins in infected and uninfected cells; however the mechanisms involved remain unclear. Using a human neuronal cell line, we found that Vpr can be taken up by neurons causing: (i) deregulation of calcium homeostasis, (ii) endoplasmic reticulum-calcium release, (iii) activation of the oxidative stress pathway, (iv) mitochondrial dysfunction and vsynaptic retraction. In search for the cellular factors involved, we performed microRNAs and gene array assays using human neurons (primary cultures or cell line, SH-SY5Y) that we treated with recombinant Vpr proteins. Interestingly, Vpr deregulates the levels of several microRNAs (e.g. miR-34a) and their target genes (e.g. CREB), which could lead to neuronal dysfunctions. Therefore, we conclude that Vpr plays a major role in neuronal dysfunction through deregulating microRNAs and their target genes, a phenomenon that could lead to the development of neurocognitive disorders.Although effective in prolonging the life expectancy in patients with HIV infection (1), the highly active antiretroviral therapy (HAART) 2 in fact has resulted in an increased prevalence of HIV-associated neurocognitive disorders (HAND) (2). The molecular mechanisms leading to this phenomenon remain to be elucidated. Several reports indicated that HIVinfected macrophages and microglia produce neurotoxins (e.g. viral and cellular proteins) that have the ability to cause neuronal deregulation and to promote HAND (3, 4). The viral protein R (Vpr) is among the released HIV-1 proteins that have been considered to be deleterious to neurons; however the molecular mechanisms involved remain unclear (5-7). Vpr is packaged into the virion, and is essential for HIV-1 replication in macrophages (8, 9). Infected brain cells have been shown to release Vpr that could affects neuronal growth (10). Vpr mediates multiple functions, including nuclear import of the HIV-1 pre-integration complex, G 2 cell cycle arrest, transactivation of both viral replication, and host genes and induction of apoptosis (11,12). Vpr was also detected in a soluble form in CSF and sera of HIV-infected patients displaying neurological disorders (10). Vpr causes neuronal degeneration both in vitro and in vivo (7,10,13).A calcium channel is an ion channel, which displays selective permeability to Ca 2ϩ ions. It is sometimes synonymous as voltage-dependent Ca 2ϩ channel (VDCC) (14). Activation of particular VDCCs allows Ca 2ϩ entry into the cell, which depending on the cell type, results in muscular contraction, excitation of neurons, up-regulation of gene expression, or release of neuro...

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“…injection (40 l) on days 0, 3, 7, 14, 21, and 28 (3 doses in the first week, followed by weekly dosing for another 3 weeks) over 4 weeks. Blood samples were collected on days 1,3,7,8,14,15,21,22,28, and 29. On day 35, half the mice in each group (n ϭ 5) were sacrificed and tissues and blood samples were collected.…”

Section: Chemicalsmentioning

confidence: 99%

“…ART has transformed HIV disease into a long-term manageable disorder (1,2). However, treatment failure and related drug resistance remain an issue with ART, which can contribute to suboptimal drug efficacy, variable pharmacokinetics, poor adherence to lifelong therapy, comorbid conditions, substance abuse, and inherent ART toxicities (3)(4)(5).…”

mentioning

confidence: 99%

Pharmacokinetics, Biodistribution, and Toxicity of Folic Acid-Coated Antiretroviral Nanoformulations

Gautam

Puligujja

Balkundi

et al. 2014

Antimicrob Agents Chemother

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The drug delivery platform for folic acid (FA)-coated nanoformulated ritonavir (RTV)-boosted atazanavir (FA-nanoATV/r) using poloxamer 407 was developed to enhance cell and tissue targeting for a range of antiretroviral drugs. Such formulations would serve to extend the drug half-life while improving the pharmacokinetic profile and biodistribution to reservoirs of human immunodeficiency virus (HIV) infection. To this end, we now report enhanced pharmacokinetics and drug biodistribution with limited local and systemic toxicities of this novel nanoformulation. The use of FA as a targeting ligand for nanoATV/r resulted in plasma and tissue drug concentrations up to 200-fold higher compared to equimolar doses of native drug. In addition, ATV and RTV concentrations in plasma from mice on a folate-deficient diet were up to 23-fold higher for mice administered FA-nanoATV/r than for mice on a normal diet. Compared to earlier nanoATV/r formulations, FA-nanoATV/r resulted in enhanced and sustained plasma and tissue ATV concentrations. In a drug interaction study, ATV plasma and tissue concentrations were up to 5-fold higher in mice treated with FA-nanoATV/r than in mice treated with FA-nanoATV alone. As observed in mice, enhanced and sustained plasma concentrations of ATV were observed in monkeys. NanoATV/r was associated with transient local inflammation at the site of injection. There were no systemic adverse reactions associated with up to 10 weeks of chronic exposure of mice or monkeys to FA-nanoATV/r. R emarkable progress was realized in the global effort to defeat human immunodeficiency virus (HIV) infection through effective antiretroviral therapy (ART). ART has transformed HIV disease into a long-term manageable disorder (1, 2). However, treatment failure and related drug resistance remain an issue with ART, which can contribute to suboptimal drug efficacy, variable pharmacokinetics, poor adherence to lifelong therapy, comorbid conditions, substance abuse, and inherent ART toxicities (3-5). These, we posit, can be addressed by developing long-acting and targeted ART.Long-acting nanoformulated ART (nanoART) can achieve enhanced and sustained steady-state drug concentrations with infrequent dosing in mice (6-9). NanoART treatment resulted in marked improvements in the pharmacokinetic (PK) and pharmacodynamic (PD) profiles in normal and humanized mouse models (9-11). This effect is mediated by mononuclear phagocytes (MP; monocytes, macrophages, and dendritic cells), which can act as reservoirs and transporters of HIV-1 and could also potentially facilitate drug uptake, transport, and release of nanoART (8,(12)(13)(14). We have demonstrated that the improved PK profile of nano-ART over those of unformulated drugs, at least in part, is the result of the sustained release of protease inhibitors from the site of drug injection and from macrophages present in tissues (9). However, our first nanoART formulation, using poloxamer 188 (P188)-encased drug, demonstrated shortcomings that may hamper clinical translation. These i...

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HIV and antiretroviral therapy in the brain: neuronal injury and repair

Cited by 466 publications

References 144 publications

HIV-1 Tat Protein Promotes Neuronal Dysfunction through Disruption of MicroRNAs

HIV-1 Tat Protein Promotes Neuronal Dysfunction through Disruption of MicroRNAs

Deregulation of microRNAs by HIV-1 Vpr Protein Leads to the Development of Neurocognitive Disorders

Pharmacokinetics, Biodistribution, and Toxicity of Folic Acid-Coated Antiretroviral Nanoformulations

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