tetano
Editor, Senior Moderator
Cell
. 2021 Nov 10;S0092-8674(21)01319-2.
doi: 10.1016/j.cell.2021.11.004. Online ahead of print.
Identification of a therapeutic interfering particle-A single-dose SARS-CoV-2 antiviral intervention with a high barrier to resistance
Sonali Chaturvedi[SUP] 1 [/SUP], Gustavo Vasen[SUP] 2 [/SUP], Michael Pablo[SUP] 2 [/SUP], Xinyue Chen[SUP] 2 [/SUP], Nathan Beutler[SUP] 3 [/SUP], Arjun Kumar[SUP] 2 [/SUP], Elizabeth Tanner[SUP] 2 [/SUP], Sylvia Illouz[SUP] 4 [/SUP], Donna Rahgoshay[SUP] 4 [/SUP], John Burnett[SUP] 5 [/SUP], Leo Holguin[SUP] 5 [/SUP], Pei-Yi Chen[SUP] 6 [/SUP], Blaise Ndjamen[SUP] 7 [/SUP], Melanie Ott[SUP] 6 [/SUP], Robert Rodick[SUP] 4 [/SUP], Thomas Rogers[SUP] 3 [/SUP], Davey M Smith[SUP] 3 [/SUP], Leor S Weinberger[SUP] 8 [/SUP]
Affiliations
Abstract
Viral-deletion mutants that conditionally replicate and inhibit the wild-type virus (i.e., defective interfering particles, DIPs) have long been proposed as single-administration interventions with high genetic barriers to resistance. However, theories predict that robust, therapeutic DIPs (i.e., therapeutic interfering particles, TIPs) must conditionally spread between cells with R[SUB]0[/SUB] >1. Here, we report engineering of TIPs that conditionally replicate with SARS-CoV-2, exhibit R[SUB]0[/SUB] >1, and inhibit viral replication 10- to 100-fold. Inhibition occurs via competition for viral replication machinery, and a single administration of TIP RNA inhibits SARS-CoV-2 sustainably in continuous cultures. Strikingly, TIPs maintain efficacy against neutralization-resistant variants (e.g., B.1.351). In hamsters, both prophylactic and therapeutic intranasal administration of lipid-nanoparticle TIPs durably suppressed SARS-CoV-2 by 100-fold in the lungs, reduced pro-inflammatory cytokine expression, and prevented severe pulmonary edema. These data provide proof of concept for a class of single-administration antivirals that may circumvent current requirements to continually update medical countermeasures against new variants.
Keywords: RNA; SARS-CoV-2; coronavirus; defective interfering particles; evolution; intranasal; lipid nanoparticle; therapeutic interfering particles; variants; virus-like particle.
. 2021 Nov 10;S0092-8674(21)01319-2.
doi: 10.1016/j.cell.2021.11.004. Online ahead of print.
Identification of a therapeutic interfering particle-A single-dose SARS-CoV-2 antiviral intervention with a high barrier to resistance
Sonali Chaturvedi[SUP] 1 [/SUP], Gustavo Vasen[SUP] 2 [/SUP], Michael Pablo[SUP] 2 [/SUP], Xinyue Chen[SUP] 2 [/SUP], Nathan Beutler[SUP] 3 [/SUP], Arjun Kumar[SUP] 2 [/SUP], Elizabeth Tanner[SUP] 2 [/SUP], Sylvia Illouz[SUP] 4 [/SUP], Donna Rahgoshay[SUP] 4 [/SUP], John Burnett[SUP] 5 [/SUP], Leo Holguin[SUP] 5 [/SUP], Pei-Yi Chen[SUP] 6 [/SUP], Blaise Ndjamen[SUP] 7 [/SUP], Melanie Ott[SUP] 6 [/SUP], Robert Rodick[SUP] 4 [/SUP], Thomas Rogers[SUP] 3 [/SUP], Davey M Smith[SUP] 3 [/SUP], Leor S Weinberger[SUP] 8 [/SUP]
Affiliations
- PMID: 34838159
- DOI: 10.1016/j.cell.2021.11.004
Abstract
Viral-deletion mutants that conditionally replicate and inhibit the wild-type virus (i.e., defective interfering particles, DIPs) have long been proposed as single-administration interventions with high genetic barriers to resistance. However, theories predict that robust, therapeutic DIPs (i.e., therapeutic interfering particles, TIPs) must conditionally spread between cells with R[SUB]0[/SUB] >1. Here, we report engineering of TIPs that conditionally replicate with SARS-CoV-2, exhibit R[SUB]0[/SUB] >1, and inhibit viral replication 10- to 100-fold. Inhibition occurs via competition for viral replication machinery, and a single administration of TIP RNA inhibits SARS-CoV-2 sustainably in continuous cultures. Strikingly, TIPs maintain efficacy against neutralization-resistant variants (e.g., B.1.351). In hamsters, both prophylactic and therapeutic intranasal administration of lipid-nanoparticle TIPs durably suppressed SARS-CoV-2 by 100-fold in the lungs, reduced pro-inflammatory cytokine expression, and prevented severe pulmonary edema. These data provide proof of concept for a class of single-administration antivirals that may circumvent current requirements to continually update medical countermeasures against new variants.
Keywords: RNA; SARS-CoV-2; coronavirus; defective interfering particles; evolution; intranasal; lipid nanoparticle; therapeutic interfering particles; variants; virus-like particle.