Identification of a therapeutic interfering particle—A single-dose SARS-CoV-2 antiviral intervention with a high barrier to resistance

Chaturvedi, Sonali; Vasen, Gustavo; Pablo, Michael; Chen, Xinyue; Beutler, Nathan; Kumar, Arjun J; Tanner, Elizabeth J.; Illouz, Sylvia E. Moortgat; Rahgoshay, Donna; Burnett, J.; Holguin, Leo; Chen, Peiyi; Ndjamen, Blaise; Ott, Mélanie; Rodick, Robert; Rogers, Thomas F.; Smith, Davey M; Weinberger, Leor S.

doi:10.1016/j.cell.2021.11.004

Cited by 54 publications

(92 citation statements)

References 77 publications

(98 reference statements)

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“…The TIPs were tested in cell culture, human lung organoids, and in hamsters. The engineered TIPs were found to inhibit SARS-CoV-2 replication by 10 to 100-fold in cells, and suppressed virus load by 10-fold in the lungs of hamsters, and reduced inflammation and severe disease when administered pre-or post-infection [154]. These encouraging results provide hope for eventual testing and optimization in human clinical trials.…”

Section: Dips As Antiviral Therapiesmentioning

confidence: 82%

Virus-like Particles: Measures and Biological Functions

Bhat

Cao

Yin

2022

Viruses

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Virus-like particles resemble infectious virus particles in size, shape, and molecular composition; however, they fail to productively infect host cells. Historically, the presence of virus-like particles has been inferred from total particle counts by microscopy, and infectious particle counts or plaque-forming-units (PFUs) by plaque assay; the resulting ratio of particles-to-PFUs is often greater than one, easily 10 or 100, indicating that most particles are non-infectious. Despite their inability to hijack cells for their reproduction, virus-like particles and the defective genomes they carry can exhibit a broad range of behaviors: interference with normal virus growth during co-infections, cell killing, and activation or inhibition of innate immune signaling. In addition, some virus-like particles become productive as their multiplicities of infection increase, a sign of cooperation between particles. Here, we review established and emerging methods to count virus-like particles and characterize their biological functions. We take a critical look at evidence for defective interfering virus genomes in natural and clinical isolates, and we review their potential as antiviral therapeutics. In short, we highlight an urgent need to better understand how virus-like genomes and particles interact with intact functional viruses during co-infection of their hosts, and their impacts on the transmission, severity, and persistence of virus-associated diseases.

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Section: Dips As Antiviral Therapiesmentioning

confidence: 82%

Virus-like Particles: Measures and Biological Functions

Bhat

Cao

Yin

2022

Viruses

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“…Short 24-nt RNAs containing a tetramer repeat of the TRS (termed FD TRS ) were engineered, and to ensure that these short RNAs did not activate innate immune responses, a size-matched scrambled FD RNA (FD Scram ) was used as a negative control. Cells were transfected with FD TRS RNAs and infected with SARS-CoV-2 isolate WA-1 (MOI = 0.05), and the effects on replication were examined as described ( Chaturvedi et al., 2021 ). As predicted, during the first viral replication cycle (∼8 h), FD TRS RNAs induced a significant increase in both sub-genomic and genomic viral RNAs, including NSP15, ORF1a, and Spike RNA ( Figures 7 B and S7 A).…”

Section: Resultsmentioning

confidence: 99%

Disrupting autorepression circuitry generates “open-loop lethality” to yield escape-resistant antiviral agents

Chaturvedi

Pablo

Wolf

et al. 2022

Cell

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“…These TIPs also reduced pro-inflammatory cytokines, and prevented pulmonary edema. The mechanism of SARS-CoV-2 inhibition by these TIPs was proposed to be due to competition for viral trans elements and no stimulation of innate immunity was recorded [ 42 ].…”

Section: Strategiesmentioning

confidence: 99%

A Defective Viral Particle Approach to COVID-19

Kalamvoki

Norris

2022

Cells

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The novel coronavirus SARS-CoV-2 has caused a pandemic resulting in millions of deaths worldwide. While multiple vaccines have been developed, insufficient vaccination combined with adaptive mutations create uncertainty for the future. Here, we discuss novel strategies to control COVID-19 relying on Defective Interfering Particles (DIPs) and related particles that arise naturally during an infection. Our intention is to encourage and to provide the basis for the implementation of such strategies by multi-disciplinary teams. We therefore provide an overview of SARS-CoV-2 for a multi-disciplinary readership that is specifically tailored to these strategies, we identify potential targets based on the current knowledge of the properties and functions of coronaviruses, and we propose specific strategies to engineer DIPs and other interfering or therapeutic nanoparticles.

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Identification of a therapeutic interfering particle—A single-dose SARS-CoV-2 antiviral intervention with a high barrier to resistance

Cited by 54 publications

References 77 publications

Virus-like Particles: Measures and Biological Functions

Virus-like Particles: Measures and Biological Functions

Disrupting autorepression circuitry generates “open-loop lethality” to yield escape-resistant antiviral agents

A Defective Viral Particle Approach to COVID-19

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