The Paradox of HIV Blood–Brain Barrier Penetrance and Antiretroviral Drug Delivery Deficiencies

Osborne, Olivia; Peyravian, Nadia; Nair, Madhavan; Daunert, Sylvia; Toborek, Michał

doi:10.1016/j.tins.2020.06.007

Cited by 96 publications

(83 citation statements)

References 95 publications

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“…Microglia are the main cell type supporting productive HIV-1 infection and generating a HIV-1 reservoir in the brain (50,(69)(70)(71)(72). After infection with HIV-1, mRNA and protein expression of ACE2 and TMPRSS2 was evaluated by qPCR and immunoblotting, respectively.…”

Section: Hiv-1 Infection Of Human Microglial Cells Upregulates Ace2 Amentioning

confidence: 99%

Expression of SARS-CoV-2-related Receptors in Cells of the Neurovascular Unit: Implications for HIV-1 Infection

Torices

Cabrera

Stangis

et al. 2021

Preprint

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Background. Neurological complications are common in patients affected by COVID-19 due to the ability of SARS-CoV-2 to infect brains. While the mechanisms of this process are not fully understood, it has been proposed that SARS-CoV-2 can infect the cells of the neurovascular units (NVU), which form the blood-brain barrier (BBB). The aim of the current study was to analyze the expression pattern of the main SARS-CoV-2 receptors in naïve and HIV-1-infected cells of the NVU in order to elucidate a possible pathway of the virus entry into the brain and a potential modulatory impact of HIV-1 in this process. Methods. The gene and protein expression profile of ACE2, TMPRSS2, ADAM17, BSG, DPP4, AGTR2, ANPEP, cathepsin B and cathepsin L was assessed by qPCR and immunoblotting, respectively. In addition, we investigated if brain endothelial cells can be affected by the exposure to the S1 subunit of the S protein, the domain responsible for the direct binding of SARS-CoV-2 to the ACE2 receptors. Results. The receptors involved in SARS-CoV-2 infection are coexpressed in the cells of the NVU, especially in astrocytes and microglial cells. These receptors are functionally active as exposure of endothelial cells to the SARS CoV-2 S1 protein subunit altered the expression pattern of tight junction proteins, such as claudin-5 and ZO-1. Additionally, HIV-1 infection upregulated ACE2 and TMPRSS2 expression in brain astrocytes and microglia cells.Conclusions. These findings provide key insight into SARS-CoV-2 recognition by cells of the NVU and may help to develop possible treatment of CNS complications of COVID-19.

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Section: Hiv-1 Infection Of Human Microglial Cells Upregulates Ace2 Amentioning

confidence: 99%

Expression of SARS-CoV-2-related Receptors in Cells of the Neurovascular Unit: Implications for HIV-1 Infection

Torices

Cabrera

Stangis

et al. 2021

Preprint

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“…There is an ongoing debate if HIV-related brain pathology is better associated with viral load or rather with ongoing chronic inflammatory responses [38]. Taking into consideration a relatively minor brain infection by EcoHIV, our model may reflect the influence of microenvironmental changes that occur as a consequence of microglial or astroglial infection and/or upregulated neuroinflammatory responses.…”

Section: Discussionmentioning

confidence: 99%

Methamphetamine Enhances HIV-Induced Aberrant Proliferation of Neural Progenitor Cells via the FOXO3-Mediated Mechanism

et al. 2021

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Maintaining an intact pool of neural progenitor cells (NPCs) is crucial for generating new and functionally active neurons. Methamphetamine (METH) can exacerbate the HIV-induced deficit of adult neurogenesis; however, potential mechanisms of this influence are still poorly understood. In the present study, we present evidence that chronic exposure to METH combined with brain infection by EcoHIV results in enhanced proliferation of NPCs in the subventricular zone (SVZ) in mice. This effect was long-lasting as it was preserved ex vivo in NPCs isolated from the exposed mice over several passages in the absence of additional treatments. Increased proliferation in response to METH plus HIV was associated with dysregulation of cyclin B1 and cyclin D. Transcriptomic studies indicated that 27 out of the top 30 differentially expressed genes in response to METH plus EcoHIV were targets of the forkhead box O transcriptional factor (FOXO) and primarily FOXO3. Additional ex vivo studies and in vitro experiments using human NPCs exposed to METH and infected with HIV revealed upregulation of the CXCL12-CXCR4 axis, leading to activation of downstream pAkt and pErk, the pathways that can phosphorylate FOXO3 and force its exports from the nuclei into the cytoplasm. Indeed, nuclear expulsion of FOXO3 was demonstrated both in mice exposed to METH and infected with EcoHIV and in cell cultures of human NPCs. These results provide novel information that exposure to METH combined with HIV infection can induce aberrant proliferation of SVZ-derived NPCs and identifies CXCL12-CXCR4-Akt-1-mediated phosphorylation of FOXO3 as the mechanism responsible for this effect.

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“…For HIV-1 there is currently a need for more effective delivery platforms compatible with antiretroviral drugs. Specifically, a productive CNS delivery of such compounds is expected to reduce HIV-1-associated neurological disorders as well as to reduce HIV-1 replication at this sanctuary site [ 13 , 50 – 51 ].…”

Section: Discussionmentioning

confidence: 99%

“…In order to reach safer therapeutic options for treatment of brain diseases and disorders, a productive drug transport across the blood-brain barrier (BBB) is critical. For example, despite successful implementation of antiretroviral drugs for the treatment of human immunodeficiency virus 1 (HIV-1), HIV-1-associated neurological disorders persist due to the poor uptake of antiretroviral drugs across the BBB [12][13][14]. There are two ways to traverse the BBB, one is through temporary disruption of the physical barrier, which impairs BBB function, and the other is to use nanocarriers or particles [11].…”

Section: Introductionmentioning

confidence: 99%

Enhanced target cell specificity and uptake of lipid nanoparticles using RNA aptamers and peptides

Ray¹,

Hansen²,

Taskova³

et al. 2021

Beilstein J. Org. Chem.

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Lipid nanoparticles (LNPs) constitute a facile and scalable approach for delivery of payloads to human cells. LNPs are relatively immunologically inert and can be produced in a cost effective and scalable manner. However, targeting and delivery of LNPs across the blood–brain barrier (BBB) has proven challenging. In an effort to target LNPs composed of an ionizable cationic lipid (DLin-MC3-DMA), cholesterol, the phospholipid 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), and 1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000 (DMG-PEG 2000) to particular cell types, as well as to generate LNPs that can cross the BBB, we developed and assessed two approaches. The first was centered on the BBB-penetrating trans-activator of transcription (Tat) peptide or the peptide T7, and the other on RNA aptamers targeted to glycoprotein gp160 from human immunodeficiency virus (HIV) or C-C chemokine receptor type 5 (CCR5), a HIV-1 coreceptor. We report herein a CCR5-selective RNA aptamer that acts to facilitate entry through a simplified BBB model and that drives the uptake of LNPs into CCR5-expressing cells, while the gp160 aptamer did not. We further observed that the addition of cell-penetrating peptides, Tat and T7, did not increase BBB penetration above the aptamer-loaded LNPs alone. Moreover, we found that these targeted LNPs exhibit low immunogenic and low toxic profiles and that targeted LNPs can traverse the BBB to potentially deliver drugs into the target tissue. This approach highlights the usefulness of aptamer-loaded LNPs to increase target cell specificity and potentially deliverability of central-nervous-system-active RNAi therapeutics across the BBB.

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The Paradox of HIV Blood–Brain Barrier Penetrance and Antiretroviral Drug Delivery Deficiencies

Cited by 96 publications

References 95 publications

Expression of SARS-CoV-2-related Receptors in Cells of the Neurovascular Unit: Implications for HIV-1 Infection

Expression of SARS-CoV-2-related Receptors in Cells of the Neurovascular Unit: Implications for HIV-1 Infection

Methamphetamine Enhances HIV-Induced Aberrant Proliferation of Neural Progenitor Cells via the FOXO3-Mediated Mechanism

Enhanced target cell specificity and uptake of lipid nanoparticles using RNA aptamers and peptides

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