The antiviral state of the cell: lessons from SARS-CoV-2

Abstract

In this review, we provide an overview of the intricate host-virus interactions that have emerged from the study of SARS-CoV-2 infection. We focus on the antiviral mechanisms of interferon-stimulated genes (ISGs) and their modulation of viral entry, replication, and release. We explore the role of a selection ISGs, including BST2, CD74, CH25H, DAXX, IFI6, IFITM1-3, LY6E, NCOA7, PLSCR1, OAS1, RTP4, and ZC3HAV1/ZAP, in restricting SARS-CoV-2 infection and discuss the virus's countermeasures. By synthesizing the latest research on SARS-CoV-2 and host antiviral responses, this review aims to provide a deeper understanding of the antiviral state of the cell under SARS-CoV-2 and other viral infections, offering insights for the development of novel antiviral strategies and therapeutics.

Figure 1.. Selected human ISGs influencing the SARS-CoV-2 replication cycle.

Not all ISGs influencing SARS-CoV-2 infection are included in this diagram. ISGs restricting SARS-CoV-2 entry: CD74 restricts virus-cell membrane fusion by inhibiting the processing of viral structural proteins by endolysosomal cathepsins [20,27]. CH25H facilitates cholesterol sequestration from the ER membrane to lipid droplets via ACAT, which indirectly leads to a decrease in cholesterol at the endosomal and plasma membranes. This decrease in cholesterol level impedes virus-cell membrane fusion and viral entry [28,29]. LY6E and PLSCR1 impede virus-cell membrane fusion via currently undetermined mechanisms [25,26,30]. NCOA7 increases lysosome acidification, leading to viral antigen degradation by lysosomal proteases [31,32]. ISGs restricting SARS-CoV-2 post-entry: DAXX translocates from the nucleus to the sites of SARS-CoV-2 replication during infection, where it likely restricts it [23]. SARS-CoV-2 papain-like protease (PLpro), part of the nsp3 protein, degrades DAXX as an evasion mechanism to counteract host antiviral responses [23]. IFI6 normally localizes to the ER [24]. It restricts SARS-CoV- 2 via currently undetermined mechanisms [23,26,33]. RTP4 binds to the the viral genomic RNA, inhibiting its replication [33,34]. OAS1 detects viral double-stranded RNA and activates RNase L [,,–40]. ISGs restricting SARS-CoV-2 exit: BST2 blocks virus release by tethering the virion to the cell membrane [41]. SARS-CoV- 2 proteins ORF7a and spike impair BST2’s antiviral function [–43]. ISGs with dual roles in SARS-CoV-2 infection: IFITM1,2,3 are known to modulate virus-cell membrane fusion; however, their influence in SARS-CoV-2 infection remains debated, with both proviral and antiviral effects reported [–53]. ZC3HAV1/ZAP impairs SARS-CoV-2 protein production by inhibiting programmed ribosomal frameshifting (antiviral effect) [54,55], yet it also facilitates the creation of ER-derived double-membrane vesicles essential for SARS-CoV-2 replication (proviral effect) [26,56].