Immune Checkpoints in Viral Infections

Abstract

As evidence has mounted that virus-infected cells, such as cancer cells, negatively regulate the function of T-cells via immune checkpoints, it has become increasingly clear that viral infections similarly exploit immune checkpoints as an immune system escape mechanism. Although immune checkpoint therapy has been successfully used in cancer treatment, numerous studies have suggested that such therapy may also be highly relevant for treating viral infection, especially chronic viral infections. However, it has not yet been applied in this manner. Here, we reviewed recent findings regarding immune checkpoints in viral infections, including COVID-19, and discussed the role of immune checkpoints in different viral infections, as well as the potential for applying immune checkpoint blockades as antiviral therapy.

Keywords: chronic infection; immune checkpoint; immunotherapy; virus.

Figure 1

Mechanism of immune checkpoint-mediated T-cell inactivation. ①: PD-1/PD-L1 inhibits the PI3K/AKT pathway or ZAP70 phosphorylation by recruiting SHP2 phosphatase; ②: CTLA-4 competitively binds to the B7 ligand of CD28 and directly inhibits Akt by activating the phosphatase PP2A, and induces proapoptotic protein BIM; ③: TIM-3/Gal-9 releases Bat3, the molecule that binds to the intracellular tail of Tim-3, which allows Tim3 to bind to Lck or PLC-γ, leading to NF-κB and NFAT inhibition; ④: BTLA/HVEM recruits SHP-1, leading to the inhibition of LCK-dependent T-cell activation; ⑤: TIGIT/CD155 directly inhibits T-cell activation and proliferation by countering the costimulatory function of CD226, and also inhibits PI3K and MAPK signaling pathway by recruiting SHIP-1; ⑥: Lag-3 downregulates T-cell activation through a still unclear mechanism. Abbreviations: ITAMs, immunoreceptor tyrosine-based activation motif l; LCK, lymphocyte-specific protein tyrosine kinase; ZAP70, zeta chain of T-cell receptor associated protein kinase 70; PLC-γ, Phospholipase C-γ; PI3K, phosphatidylinositol 3-kinase; PIP3, phosphatidylinositol (3,4,5)-trisphosphate; PIP2, phosphatidyl inositol(4,5) bisphosphate; IP3, inositol-1,4,5-trisphosphate; DAG, diacylglycerol; PKC, protein kinase C; CaN, Calcineurin; IKK, inhibitor of nuclear factor kappa-B kinase; Akt, protein kinase B (Also known as PKB or Rac); PP2A, Protein phosphatase 2 A; Ras/MEK/MAPK, Ras GTPase-protein/MAP kinase kinase/MAP kinase pathway; mTORC1, mammalian target of rapamycin complex 1; NFAT, nuclear factor of activated T-cells; pNFAT, phospho NFAT; AP-1, activator protein 1; NF-κB, nuclear factor-κB.