Gene editing and elimination of latent herpes simplex virus in vivo DOI Creative Commons
Martine Aubert, Daniel E. Strongin, Pavitra Roychoudhury

et al.

Nature Communications, Journal Year: 2020, Volume and Issue: 11(1)

Published: Aug. 18, 2020

Abstract We evaluate gene editing of HSV in a well-established mouse model, using adeno-associated virus (AAV)-delivered meganucleases, as potentially curative approach to treat latent infection. Here we show that AAV-delivered but not CRISPR/Cas9, mediate highly efficient HSV, eliminating over 90% from superior cervical ganglia. Single-cell RNA sequencing demonstrates both and individual AAV serotypes are non-randomly distributed among neuronal subsets ganglia, implying improved delivery all may lead even more complete elimination HSV. As predicted, meganucleases triple serotype combination results the greatest decrease ganglionic loads. The levels observed these studies, if translated humans, would likely significantly reduce reactivation, shedding, lesions. Further optimization meganuclease activity is possible, offer pathway cure for

Language: Английский

The Paradox of HIV Blood–Brain Barrier Penetrance and Antiretroviral Drug Delivery Deficiencies DOI Creative Commons
Olivia M. Osborne, Nadia Peyravian, Madhavan Nair

et al.

Trends in Neurosciences, Journal Year: 2020, Volume and Issue: 43(9), P. 695 - 708

Published: July 15, 2020

HIV attacks the body's immune cells, frequently compromises integrity of blood-brain barrier (BBB), and infects CNS in early stages infection. Dysfunction BBB further potentiates viral replication within CNS, which can lead to HIV-associated neuropathology. Antiretroviral therapy (ART) significantly improves patient outcomes reduces mortality rates. However, there has been limited progress targeting latent reservoirs may eventually rebound viremia. While ART drugs are shown be effective attenuating periphery, protection brain by offers an isolated sanctuary harbor maintains chronic persistent CNS. In this review, we elucidate pathology BBB, its ability potentiate replication, as well current therapies insufficiencies treating HIV-infected individuals.

Language: Английский

Citations

127
Why and where an HIV cure is needed and how it might be achieved DOI
Thumbi Ndung’u, Joseph M. McCune, Steven G. Deeks

et al.

Nature, Journal Year: 2019, Volume and Issue: 576(7787), P. 397 - 405

Published: Dec. 18, 2019

Language: Английский

Citations

123
A year-long extended release nanoformulated cabotegravir prodrug DOI
Tanmay A. Kulkarni, Aditya N. Bade, Brady Sillman

et al.

Nature Materials, Journal Year: 2020, Volume and Issue: 19(8), P. 910 - 920

Published: April 27, 2020

Language: Английский

Citations

96
Extinction of all infectious HIV in cell culture by the CRISPR-Cas12a system with only a single crRNA DOI Creative Commons
Zongliang Gao,

Ming-Hui Fan,

Atze T. Das

et al.

Nucleic Acids Research, Journal Year: 2020, Volume and Issue: 48(10), P. 5527 - 5539

Published: April 8, 2020

Abstract The CRISPR-Cas9 system has been used for genome editing of various organisms. We reported inhibition the human immunodeficiency virus (HIV) in cell culture infections with a single guide RNA (gRNA) and subsequent viral escape, but complete inactivation infectious HIV certain combinations two gRNAs. new RNA-guided endonuclease CRISPR-Cas12a (formerly Cpf1) may provide more promising tool engineering increased activity specificity. compared Cas12a to original Cas9 integrated DNA genome. Superior antiviral is Cas12a, which can achieve full only gRNA (called crRNA). propose that different architecture versus explains this effect. also disclose cleavage by repair causes mutations sequence profile distinct from Cas9. Both CRISPR systems induce typical small deletions around site repair, does not pure insertions are routinely observed Although these signatures apparent many literature studies, first report documents striking differences.

Language: Английский

Citations

94
Single-cell transcriptional landscapes reveal HIV-1–driven aberrant host gene transcription as a potential therapeutic target DOI
Runxia Liu, Yang-Hui Jimmy Yeh, Ales Varabyou

et al.

Science Translational Medicine, Journal Year: 2020, Volume and Issue: 12(543)

Published: May 13, 2020

Single-cell transcriptome analysis by HIV-1 SortSeq identifies HIV-1–driven aberrant host gene transcription as a mechanism of persistence.

Language: Английский

Citations

94
CRISPR based editing of SIV proviral DNA in ART treated non-human primates DOI Creative Commons
Pietro Mancuso, Chen Chen, Rafal Kaminski

et al.

Nature Communications, Journal Year: 2020, Volume and Issue: 11(1)

Published: Nov. 27, 2020

Abstract Elimination of HIV DNA from infected individuals remains a challenge in medicine. Here, we demonstrate that intravenous inoculation SIV-infected macaques, well-accepted non-human primate model infection, with adeno-associated virus 9 (AAV9)-CRISPR/Cas9 gene editing construct designed for eliminating proviral SIV DNA, leads to broad distribution molecules and precise cleavage removal fragments the integrated genome blood cells tissues known be viral reservoirs including lymph nodes, spleen, bone marrow, brain among others. Accordingly, AAV9-CRISPR treatment results reduction percent tissues. These proof-of-concept observations offer promising step toward elimination clinic.

Language: Английский

Citations

82
Detect and destroy: CRISPR-based technologies for the response against viruses DOI Creative Commons
Catherine A. Freije, Pardis C. Sabeti

Cell Host & Microbe, Journal Year: 2021, Volume and Issue: 29(5), P. 689 - 703

Published: April 28, 2021

Despite numerous viral outbreaks in the last decade, including a devastating global pandemic, diagnostic and therapeutic technologies remain severely lacking. CRISPR-Cas systems have potential to address these critical needs response against infectious disease. Initially discovered as bacterial adaptive immune system, provide unique opportunity create programmable, sequence-specific for detection of nucleic acids inhibition replication. This review summarizes how systems—in particular recently DNA-targeting Cas12 RNA-targeting Cas13, both possessing trans-cleavage activity—are being harnessed diagnostics therapies. We further highlight whose development has accelerated COVID-19 pandemic.

Language: Английский

Citations

64
CRISPR/Cas9: a tool to eradicate HIV-1 DOI Creative Commons

Ruchira Bhowmik,

Binay Chaubey

AIDS Research and Therapy, Journal Year: 2022, Volume and Issue: 19(1)

Published: Dec. 1, 2022

Abstract The development of antiretroviral therapy (ART) has been effective in suppressing HIV replication. However, severe drug toxicities due to the and its failure targeting integrated proviral genome have led introduction a new paradigm gene-based therapies. With inhibition high precision, clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein-9 nuclease (Cas9) or CRISPR/Cas9 emerged as an editing tool last decade. Mediated by guide RNAs (gRNAs), Cas9 endonuclease acts like genetic scissors that can modify specific target sites. this concept, used HIV-1 both vitro well vivo studies including non-human primates. CRISPR also tested for latent modulating transcription with help specialized mutant. Overcoming limitations current therapy, potential become primary eradicating infection. In review, we summarize recent advancements genome, challenges future prospects.

Language: Английский

Citations

45
A CRISPR-Cas Cure for HIV/AIDS DOI Open Access

Mouraya Hussein,

Mariano A. Molina, Ben Berkhout

et al.

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(2), P. 1563 - 1563

Published: Jan. 13, 2023

Human immunodeficiency virus (HIV) infections and HIV-induced acquired syndrome (AIDS) continue to represent a global health burden. There is currently no effective vaccine, nor any cure, for HIV infections; existing antiretroviral therapy can suppress viral replication, but only as long antiviral drugs are taken. infects cells of the host immune system, it establish long-lived reservoir, which be targeted edited through gene therapy. Gene editing platforms based on clustered regularly interspaced palindromic repeat-Cas system (CRISPR-Cas) have been recognized promising tools in development therapies infections. In this review, we evaluate current landscape CRISPR-Cas-based against HIV, with an emphasis infection biology well activity restriction factors. We discuss potential combined CRISPR-Cas approach that targets genes activate factors inhibit replication simultaneously. Lastly, focus challenges solutions approaches achieving cure.

Language: Английский

Citations

33
Genetically encoding multiple functionalities into extracellular vesicles for the targeted delivery of biologics to T cells DOI
Devin M. Stranford, Lacy M. Simons, Katherine E. Berman

et al.

Nature Biomedical Engineering, Journal Year: 2023, Volume and Issue: 8(4), P. 397 - 414

Published: Nov. 27, 2023

Language: Английский

Citations

32