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Deprecated: Implicit conversion from float 269.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Cell 2021 ; 184 (25): 6022-6036.e18 Nephropedia Template TP
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Identification of a therapeutic interfering particle-A single-dose SARS-CoV-2 antiviral intervention with a high barrier to resistance #MMPMID34838159
Chaturvedi S; Vasen G; Pablo M; Chen X; Beutler N; Kumar A; Tanner E; Illouz S; Rahgoshay D; Burnett J; Holguin L; Chen PY; Ndjamen B; Ott M; Rodick R; Rogers T; Smith DM; Weinberger LS
Cell 2021[Dec]; 184 (25): 6022-6036.e18 PMID34838159show ga
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(0) >1. Here, we report engineering of TIPs that conditionally replicate with SARS-CoV-2, exhibit R(0) >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.