An ACAT inhibitor suppresses SARS-CoV-2 replication and boosts antiviral T cell activity

Wing, Peter A. C., Schmidt, Nathalie M., Peters, Rory, Erdmann, Maximilian, Brown, Rachel, Wang, Hao, Swadling, Leo, Newman, Joseph, Thakur, Nazia, Shionoya, Kaho, Morgan, Sophie B., Hinks, Timothy S. C., Watashi, Koichi, Bailey, Dalan, Hansen, Scott B., Davidson, Andrew D., Maini, Mala K. and McKeating, Jane A. and COVIDsortium Investigators (2023) An ACAT inhibitor suppresses SARS-CoV-2 replication and boosts antiviral T cell activity. PLoS Pathogens, 19 (5). ISSN 1553-7374

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Abstract

The severity of disease following infection with SARS-CoV-2 is determined by viral replication kinetics and host immunity, with early T cell responses and/or suppression of viraemia driving a favourable outcome. Recent studies uncovered a role for cholesterol metabolism in the SARS-CoV-2 life cycle and in T cell function. Here we show that blockade of the enzyme Acyl-CoA:cholesterol acyltransferase (ACAT) with Avasimibe inhibits SARS-CoV-2 pseudoparticle infection and disrupts the association of ACE2 and GM1 lipid rafts on the cell membrane, perturbing viral attachment. Imaging SARS-CoV-2 RNAs at the single cell level using a viral replicon model identifies the capacity of Avasimibe to limit the establishment of replication complexes required for RNA replication. Genetic studies to transiently silence or overexpress ACAT isoforms confirmed a role for ACAT in SARS-CoV-2 infection. Furthermore, Avasimibe boosts the expansion of functional SARS-CoV-2-specific T cells from the blood of patients sampled during the acute phase of infection. Thus, re-purposing of ACAT inhibitors provides a compelling therapeutic strategy for the treatment of COVID-19 to achieve both antiviral and immunomodulatory effects.

Item Type:	Article
Depositing User:	LivePure Connector
Date Deposited:	04 Mar 2025 15:30
Last Modified:	09 Mar 2025 07:30
URI:	https://ueaeprints.uea.ac.uk/id/eprint/98663
DOI:	10.1371/journal.ppat.1011323

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