Differential Cellular Tropism of Lentivirus and Adeno-Associated Virus in the Brain of Cynomolgus Monkey

Many studies have implicated both angiotensin II (ANG II) and aldosterone (Aldo) in the pathogenesis of hypertension, the progression of renal injury, and cardiac remodeling after myocardial infarction. In several cases, ANG II and Aldo have been shown to have synergistic interactions in the periphery. In the present studies, we tested the hypothesis that ANG II and Aldo interact centrally in Aldo- and ANG II-induced hypertension in male rats. In rats with blood pressure (BP) and heart rate (HR) measured by DSI telemetry, intracerebroventricular (icv) infusions of the mineralocorticoid receptor (MR) antagonists spironolactone and RU28318 or the angiotensin type 1 receptor (AT1R) antagonist irbesartan significantly inhibited Aldo-induced hypertension. In ANG II-induced hypertension, icv infusion of RU28318 significantly reduced the increase in BP. Moreover, icv infusions of the reactive oxygen species (ROS) scavenger tempol or the NADPH oxidase inhibitor apocynin attenuated Aldo-induced hypertension. To confirm these effects of pharmacological antagonists, icv injections of either recombinant adeno-associated virus carrying siRNA silencers of AT1aR (AT1aR-siRNA) or MR (MR-siRNA) significantly attenuated the development of Aldo-induced hypertension. The immunohistochemical and Western blot analyses of AT1aR-siRNA- or MR-siRNA-injected rats showed a marked reduction in the expression of AT1R or MR in the paraventricular nucleus compared with scrambled siRNA rats. When animals from all studies underwent ganglionic blockade with hexamethonium, there was a smaller reduction in the fall of BP in animals receiving icv AT1R or MR antagonists. These results suggest that ANG II and Aldo interact in the brain in a mutually cooperative manner such that the functional integrity of both brain AT1R and MR are necessary for hypertension to be induced by either systemic ANG II or Aldo. The pressor effects produced by systemic ANG II or Aldo involve increased central ROS and sympathetic outflow.

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Adeno Associated Virus 9–Based Gene Therapy Delivers a Functional Monocarboxylate Transporter 8, Improving Thyroid Hormone Availability to the Brain of Mct8-Deficient Mice

Thyroid ◽

10.1089/thy.2016.0060 ◽

2016 ◽

Vol 26 (9) ◽

pp. 1311-1319 ◽

Cited By ~ 17

Author(s):

Hideyuki Iwayama ◽

Xiao-Hui Liao ◽

Lyndsey Braun ◽

Soledad Bárez-López ◽

Brian Kaspar ◽

...

Keyword(s):

Gene Therapy ◽

Thyroid Hormone ◽

Monocarboxylate Transporter ◽

Adeno Associated Virus ◽

The Brain ◽

Deficient Mice

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Unique Glycan Signatures Regulate Adeno-Associated Virus Tropism in the Developing Brain

Journal of Virology ◽

10.1128/jvi.02951-14 ◽

2015 ◽

Vol 89 (7) ◽

pp. 3976-3987 ◽

Cited By ~ 8

Author(s):

Giridhar Murlidharan ◽

Travis Corriher ◽

H. Troy Ghashghaei ◽

Aravind Asokan

Keyword(s):

Polysialic Acid ◽

Cell Types ◽

Developing Brain ◽

Specific Cell ◽

Developmentally Regulated ◽

Transport Pathways ◽

Adeno Associated Virus ◽

Viral Transport ◽

The Central Nervous System ◽

The Brain

ABSTRACTAdeno-associated viruses (AAV) are thought to spread through the central nervous system (CNS) by exploiting cerebrospinal fluid (CSF) flux and hijacking axonal transport pathways. The role of host receptors that mediate these processes is not well understood. In the current study, we utilized AAV serotype 4 (AAV4) as a model to evaluate whether ubiquitously expressed 2,3-linked sialic acid and the developmentally regulated marker 2,8-linked polysialic acid (PSA) regulate viral transport and tropism in the neonatal brain. Modulation of the levels of SA and PSA in cell culture studies using specific neuraminidases revealed possibly opposing roles of the two glycans in AAV4 transduction. Interestingly, upon intracranial injection into lateral ventricles of the neonatal mouse brain, a low-affinity AAV4 mutant (AAV4.18) displayed a striking shift in cellular tropism from 2,3-linked SA+ependymal lining to 2,8-linked PSA+migrating progenitors in the rostral migratory stream and olfactory bulb. In addition, this gain-of-function phenotype correlated with robust CNS spread of AAV4.18 through paravascular transport pathways. Consistent with these observations, altering glycan dynamics within the brain by coadministering SA- and PSA-specific neuraminidases resulted in striking changes to the cellular tropisms and transduction efficiencies of both parental and mutant vectors. We postulate that glycan signatures associated with host development can be exploited to redirect novel AAV vectors to specific cell types in the brain.IMPORTANCEViruses invade the CNS through various mechanisms. In the current study, we utilized AAV as a model to study the dynamics of virus-carbohydrate interactions in the developing brain and their impact on viral tropism. Our findings suggest that carbohydrate content can be exploited to regulate viral transport and tropism in the brain.

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Surface chemistry governs cellular tropism of nanoparticles in the brain

Nature Communications ◽

10.1038/ncomms15322 ◽

2017 ◽

Vol 8 (1) ◽

Cited By ~ 33

Author(s):

Eric Song ◽

Alice Gaudin ◽

Amanda R. King ◽

Young-Eun Seo ◽

Hee-Won Suh ◽

...

Keyword(s):

Surface Chemistry ◽

Cellular Tropism ◽

The Brain

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Circulating Anti-Wild-Type Adeno-Associated Virus Type 2 (AAV2) Antibodies Inhibit Recombinant AAV2 (rAAV2)-Mediated, but Not rAAV5-Mediated, Gene Transfer in the Brain

Journal of Virology ◽

10.1128/jvi.78.12.6344-6359.2004 ◽

2004 ◽

Vol 78 (12) ◽

pp. 6344-6359 ◽

Cited By ~ 156

Author(s):

Carmen S. Peden ◽

Corinna Burger ◽

Nicholas Muzyczka ◽

Ronald J. Mandel

Keyword(s):

Immune Response ◽

Virus Type ◽

Fluorescent Protein ◽

Natural Infection ◽

Cell Counting ◽

Wild Type ◽

Adeno Associated Virus ◽

Live Virus ◽

The Brain

ABSTRACT Epidemiological studies report that 80% of the population maintains antibodies (Ab) to wild-type (wt) adeno-associated virus type 2 (AAV2), with 30% expressing neutralizing Ab (NAb). The blood-brain barrier (BBB) provides limited immune privilege to brain parenchyma, and the immune response to recombinant AAV (rAAV) administration in the brain of a naive animal is minimal. However, central nervous system transduction in preimmunized animals remains unstudied. Vector administration may disrupt the BBB sufficiently to promote an immune response in a previously immunized animal. We tested the hypothesis that intracerebral rAAV administration and readministration would not be affected by the presence of circulating Ab to wt AAV2. Rats peripherally immunized with live wt AAV2 and naive controls were tested with single intrastriatal injections of rAAV2 encoding human glial cell line-derived neurotrophic factor (GDNF) or green fluorescent protein (GFP). Striatal readministration of rAAV2-GDNF was also tested in preimmunized and naive rats. Finally, serotype specificity of the immunization against wt AAV2 was examined by single injections of rAAV5-GFP. Preimmunization resulted in high levels of circulating NAb and prevented transduction by rAAV2 as assessed by striatal GDNF levels. rAAV2-GFP striatal transduction was also prevented by immunization, while rAAV5-GFP-mediated transduction, as assessed by stereological cell counting, was unaffected. Additionally, inflammatory markers were present in those animals that received repeated administrations of rAAV2, including markers of a cell-mediated immune response and cytotoxic damage. A live virus immunization protocol generated the circulating anti-wt-AAV Ab seen in this experiment, while human titers are commonly acquired via natural infection. Regardless, the data show that the presence of high levels of NAb against wt AAV can reduce rAAV-mediated transduction in the brain and should be accounted for in future experiments utilizing this vector.

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AAV-mediated expression of anti-tau scFvs decreases tau accumulation in a mouse model of tauopathy

Journal of Experimental Medicine ◽

10.1084/jem.20162125 ◽

2017 ◽

Vol 214 (5) ◽

pp. 1227-1238 ◽

Cited By ~ 28

Author(s):

Christina Ising ◽

Gilbert Gallardo ◽

Cheryl E.G. Leyns ◽

Connie H. Wong ◽

Hong Jiang ◽

...

Keyword(s):

Mouse Model ◽

Passive Immunization ◽

Single Chain ◽

Proinflammatory Response ◽

Adeno Associated Virus ◽

Single Chain Variable Fragments ◽

Novel Strategy ◽

Progressive Accumulation ◽

The Brain

Tauopathies are characterized by the progressive accumulation of hyperphosphorylated, aggregated forms of tau. Our laboratory has previously demonstrated that passive immunization with an anti-tau antibody, HJ8.5, decreased accumulation of pathological tau in a human P301S tau-expressing transgenic (P301S-tg) mouse model of frontotemporal dementia/tauopathy. To investigate whether the Fc domain of HJ8.5 is required for the therapeutic effect, we engineered single-chain variable fragments (scFvs) derived from HJ8.5 with variable linker lengths, all specific to human tau. Based on different binding properties, we selected two anti-tau scFvs and tested their efficacy in vivo by adeno-associated virus–mediated gene transfer to the brain of P301S-tg mice. The scFvs significantly reduced levels of hyperphosphorylated, aggregated tau in brain tissue of P301S-tg mice, associated with a decrease in detergent-soluble tau species. Interestingly, these mice showed substantial levels of scFvs in the cerebrospinal fluid without significant effects on total extracellular tau levels. Therefore, our study provides a novel strategy for anti-tau immunotherapeutics that potentially limits a detrimental proinflammatory response.

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Delivery of Human EV71 Receptors by Adeno-Associated Virus Increases EV71 Infection-Induced Local Inflammation in Adult Mice

BioMed Research International ◽

10.1155/2014/878139 ◽

2014 ◽

Vol 2014 ◽

pp. 1-12 ◽

Cited By ~ 2

Author(s):

Hung-Bo Hsiao ◽

Ai-Hsiang Chou ◽

Su-I Lin ◽

Shu-Pei Lien ◽

Chia-Chyi Liu ◽

...

Keyword(s):

Vaccine Development ◽

Scavenger Receptor ◽

Ev71 Infection ◽

Local Inflammation ◽

Mouth Diseases ◽

Adeno Associated Virus ◽

Adult Mice ◽

Class B ◽

Infected Adult ◽

The Brain

Enterovirus71 (EV71) is now recognized as an emerging neurotropic virus in Asia and one major causative agent of hand-foot-mouth diseases (HFMD). However potential animal models for vaccine development are limited to young mice. In this study, we used an adeno-associated virus (AAV) vector to introduce the human EV71 receptors P-selectin glycoprotein ligand-1 (hPSGL1) or a scavenger receptor class-B member-2 (hSCARB2) into adult ICR mice to change their susceptibility to EV71 infection. Mice were administered AAV-hSCARB2 or AAV-hPSGL1 through intravenous and oral routes. After three weeks, expression of human SCARB2 and PSGL1 was detected in various organs. After infection with EV71, we found that the EV71 viral load in AAV-hSCARB2- or AAV-hPSGL1-transduced mice was higher than that of the control mice in both the brain and intestines. The presence of EV71 viral particles in tissues was confirmed using immunohistochemistry analysis. Moreover, inflammatory cytokines were induced in the brain and intestines of AAV-hSCARB2- or AAV-hPSGL1-transduced mice after EV71 infection but not in wild-type mice. However, neurological disease was not observed in these animals. Taken together, we successfully infected adult mice with live EV71 and induced local inflammation using an AAV delivery system.

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