Human leukocyte antigen class I (HLA-I) molecules present intracellular peptides on the cell surface to enable CD8+ T cells to effectively control viral infections. Many viruses disrupt this antigen presentation pathway to evade immune detection. In this study, we demonstrate that SARS-CoV-2 Nsp1 impairs both the constitutive and interferon-γ (IFN-γ)-induced upregulation of HLA-I. Moreover, Nsp1 also blocks IFN-γ-induced expression of HLA-II. We found that, contrary to previously published work, the early SARS-CoV-2 B 1.1.7 Alpha variant lacking the accessory protein ORF8 retained full capacity to downregulate HLA-I, comparable to an ORF8-expressing wild-type isolate. While ectopic overexpression of ORF8 could reduce HLA-I surface levels, this effect was only observed at high expression levels. In contrast, moderate expression of the viral protein Nsp1 was sufficient to potently suppress both basal and IFN-γ-induced HLA-I, as well as HLA-II expression. To probe the underlying mechanism, we analyzed HLA-I-associated genes in previously published RNA-sequencing datasets and confirmed that Nsp1 reduces expression of components required for HLA-I biosynthesis and antigen processing. These findings identify Nsp1 as a key factor that impairs antigen presentation pathways, potentially contributing to the ability of SARS-CoV-2 to modulate immune recognition.

The V158F polymorphism found in the human Fc receptor CD16a (also known as FcγRIIIa) is thought to influence autoimmune disorders and responses to IgG-based therapies. V158F is known to influence the IgG affinity, and thereby triggering of the CD16a receptor expressed on various immune cells. In contrast to CD16 triggering by opsonized IgG, the mechanistic details of its interaction with soluble circulating IgG immune complexes (ICs) remain poorly understood. In this study we aimed to clarify the functional impact of the CD16a-V158F polymorphism in the context of IC-mediated diseases. We generated BW5147 reporter cells for both human CD16a V158F polymorphic variants. Using synthetic and disease-associated soluble IgG ICs, we assessed their respective functional responses, which were further validated using primary human NK cells. While both reporter cell variants bound ICs, the CD16aV but not the CD16aF reporter cells exhibited functional response to soluble ICs. This functional dichotomy was further confirmed in primary CD16+ human NK cells. We provide evidence for an intrinsic difference between V158F polymorphic variants of human CD16a in their responsiveness to soluble ICs, extending beyond the previously reported distinctions of low- and high-affinity binding. Future studies investigating genotype-dependent clinical-immunological differences could enhance our understanding of the pathophysiology in IC-mediated diseases and pave the way for potential individualized treatment strategies.