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Pathogen-specific CD8+ T cell responses restricted by the nonpolymorphic nonclassical class Ib molecule human leukocyte antigen E (HLA-E) are rarely reported in viral infections. The natural HLA-E ligand is a signal peptide derived from classical class Ia HLA molecules that interact with the NKG2/CD94 receptors to regulate natural killer cell functions, but pathogen-derived peptides can also be presented by HLA-E. Here, we describe five peptides from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that elicited HLA-E–restricted CD8+ T cell responses in convalescent patients with coronavirus disease 2019. These T cell responses were identified in the blood at frequencies similar to those reported for classical HLA-Ia–restricted anti–SARS-CoV-2 CD8+ T cells. HLA-E peptide–specific CD8+ T cell clones, which expressed diverse T cell receptors, suppressed SARS-CoV-2 replication in Calu-3 human lung epithelial cells. SARS-CoV-2 infection markedly down-regulated classical HLA class I expression in Calu-3 cells and primary reconstituted human airway epithelial cells, whereas HLA-E expression was not affected, enabling T cell recognition. Thus, HLA-E–restricted T cells could contribute to the control of SARS-CoV-2 infection alongside classical T cells. Editor's summary: CD8+ T cells expressing HLA-E have been reported in viral infection; however, it is unclear whether they contribute to the immune response against SARS-CoV-2. Yang et al. generated five stable HLA-E peptide tetramers to evaluate CD8+ T cell responses to SARS-CoV-2. HLA-E–restricted CD8+ T cells were detected at levels comparable to conventional HLA-Ia–restricted T cells in SARS-CoV-2 convalescent individuals. These HLA-E–specific CD8+ T cell clones recognized SARS-CoV-2–infected cells and suppressed viral replication. SARS-CoV-2 infection caused downregulation of classical HLA-Ia but not HLA-E in cell lines and primary human airway epithelial cells. These findings suggest that SARS-CoV-2–specific HLA-E–restricted CD8+ T cells may be advantageous when classically restricted T cells are disturbed during SARS-CoV-2 infection. —Hannah Isles [ABSTRACT FROM AUTHOR]

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. Trial registration: NCT04318314. Author summary: Cholesterol metabolism is a key element in both viral replication and immune cell signalling. We show that Avasimibe, an inhibitor of the cholesterol esterification enzyme Acyl-CoA:cholesterol acyltransferase (ACAT), potently inhibits SARS-CoV-2 entry and viral RNA replication. Importantly, Avasimibe boosts the expansion of functional SARS-CoV-2-specific T cells isolated from the blood of patients sampled during the acute phase of infection. Our findings show that Avasimibe has combined antiviral and T cell boosting properties in acute SARS-CoV-2 infection. This study reinforces an emerging picture of the importance of cholesterol metabolism in viral replication and T cell immunity, providing new insights on intrinsic anti-viral pathways that may be applicable to other viral pathogens. [ABSTRACT FROM AUTHOR]