Magnetically guided non-invasive CRISPR-Cas9/gRNA delivery across blood-brain barrier to eradicate latent HIV-1 infection

Kaushik, Ajeet; Yndart, Adriana; Atluri, Venkata Subba Rao; Tiwari, Sneham; Tomitaka, Asahi; Gupta, Purnima; Jayant, Rahul Dev; Alvarez-Carbonell, David; Khalili, Kamel; Nair, M. G.

doi:10.1038/s41598-019-40222-4

Cited by 97 publications

(86 citation statements)

References 41 publications

(41 reference statements)

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“…However, several challenges have to be overcome such as in vivo delivery in the brain and long-term toxicity before its use in the clinic and thus needs far more investigations. An original way to deliver CRISPR/cas9 guided RNA across the BBB has been developed recently and hold promises (Kaushik et al, 2019). Notably, it was shown that this non-invasive method which uses magnetically guided delivery of RNAs inhibits latent infection of microglial cells and cross the BBB in in vitro models.…”

Section: Resultsmentioning

confidence: 99%

Microglial Cells: The Main HIV-1 Reservoir in the Brain

Wallet

Rovere

Assche

et al. 2019

Front. Cell. Infect. Microbiol.

283

252

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Despite efficient combination of the antiretroviral therapy (cART), which significantly decreased mortality and morbidity of HIV-1 infection, a definitive HIV cure has not been achieved. Hidden HIV-1 in cellular and anatomic reservoirs is the major hurdle toward a functional cure. Microglial cells, the Central Nervous system (CNS) resident macrophages, are one of the major cellular reservoirs of latent HIV-1. These cells are believed to be involved in the emergence of drugs resistance and reseeding peripheral tissues. Moreover, these long-life reservoirs are also involved in the development of HIV-1-associated neurocognitive diseases (HAND). Clearing these infected cells from the brain is therefore crucial to achieve a cure. However, many characteristics of microglial cells and the CNS hinder the eradication of these brain reservoirs. Better understandings of the specific molecular mechanisms of HIV-1 latency in microglial cells should help to design new molecules and new strategies preventing HAND and achieving HIV cure. Moreover, new strategies are needed to circumvent the limitations associated to anatomical sanctuaries with barriers such as the blood brain barrier (BBB) that reduce the access of drugs.

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Section: Resultsmentioning

confidence: 99%

Microglial Cells: The Main HIV-1 Reservoir in the Brain

Wallet

Rovere

Assche

et al. 2019

Front. Cell. Infect. Microbiol.

283

252

View full text Add to dashboard Cite

show abstract

“…In addition, Kaushik et al developed a magnetic nanoformulation consisting of genome editing Cas9/gRNA bound with magneto-electric nanoparticles with the aim of targeting HIV-1 long terminal repeat, thereby stopping viral transcription and eradicating latent HIV infection. This is a very innovative approach deserving further investigation and that could potentially have clinical utility in the management of HIV infection of the brain [158].…”

Section: Approaches To Eliminating the Hiv-1 Brain Reservoirmentioning

confidence: 99%

Potential pharmacological approaches for the treatment of HIV-1 associated neurocognitive disorders

Omeragic

Kayode

Hoque

et al. 2020

Fluids Barriers CNS

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HIV associated neurocognitive disorders (HAND) are the spectrum of cognitive impairments present in patients infected with human immunodeficiency virus type 1 (HIV-1). The number of patients affected with HAND ranges from 30 to 50% of HIV infected individuals and although the development of combinational antiretroviral therapy (cART) has improved longevity, HAND continues to pose a significant clinical problem as the current standard of care does not alleviate or prevent HAND symptoms. At present, the pathological mechanisms contributing to HAND remain unclear, but evidence suggests that it stems from neuronal injury due to chronic release of neurotoxins, chemokines, viral proteins, and proinflammatory cytokines secreted by HIV-1 activated microglia, macrophages and astrocytes in the central nervous system (CNS). Furthermore, the blood-brain barrier (BBB) not only serves as a route for HIV-1 entry into the brain but also prevents cART therapy from reaching HIV-1 brain reservoirs, and therefore could play an important role in HAND. The goal of this review is to discuss the current data on the epidemiology, pathology and research models of HAND as well as address the potential pharmacological treatment approaches that are being investigated.

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“…However, this technique still requires an effective method for delivery across the BBB. To overcome this obstacle, it has been combined with magnetic nanodelivery systems, showing a significant HIV-LTR reduction, indicating a potential therapy to eliminate latent HIV infection in the brains of opioid abusers (Figure 1C) (208).…”

Section: New Technologies and Potential Therapiesmentioning

confidence: 99%

The Effects of Opioids on HIV Neuropathogenesis

et al. 2019

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HIV associated neurocognitive disorders (HAND) are a group of neurological deficits that affect approximately half of people living with HIV (PLWH) despite effective antiretroviral therapy (ART). There are currently no reliable molecular biomarkers or treatments for HAND. Given the national opioid epidemic, as well as illegal and prescription use of opioid drugs among PLWH, it is critical to characterize the molecular interactions between HIV and opioids in cells of the CNS. It is also important to study the role of opioid substitution therapies in the context of HIV and CNS damage in vitro and in vivo. A major mechanism contributing to HIV neuropathogenesis is chronic, low-level inflammation in the CNS. HIV enters the brain within 4–8 days after peripheral infection and establishes CNS reservoirs, even in the context of ART, that are difficult to identify and eliminate. Infected cells, including monocytes, macrophages, and microglia, produce chemokines, cytokines, neurotoxic mediators, and viral proteins that contribute to chronic inflammation and ongoing neuronal damage. Opioids have been shown to impact these immune cells through a variety of molecular mechanisms, including opioid receptor binding and cross desensitization with chemokine receptors. The effects of opioid use on cognitive outcomes in individuals with HAND in clinical studies is variable, and thus multiple biological mechanisms are likely to contribute to the complex relationship between opioids and HIV in the CNS. In this review, we will examine what is known about both HIV and opioid mediated neuropathogenesis, and discuss key molecular processes that may be impacted by HIV and opioids in the context of neuroinflammation and CNS damage. We will also assess what is known about the effects of ART on these processes, and highlight areas of study that should be addressed in the context of ART.

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Magnetically guided non-invasive CRISPR-Cas9/gRNA delivery across blood-brain barrier to eradicate latent HIV-1 infection

Cited by 97 publications

References 41 publications

Microglial Cells: The Main HIV-1 Reservoir in the Brain

Microglial Cells: The Main HIV-1 Reservoir in the Brain

Potential pharmacological approaches for the treatment of HIV-1 associated neurocognitive disorders

The Effects of Opioids on HIV Neuropathogenesis

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