Immune Checkpoints in Viral Infections
Abstract
:1. Introduction
2. Immune Checkpoints and Their T-cell Inactivation Pathways
3. Immune Checkpoints in HIV
3.1. HIV-Specific T-cell Exhaustion Accompanies Immune Checkpoint Upregulation
Virus | Manifestations | Checkpoints Involved | Functions | Ref. |
---|---|---|---|---|
HIV | Establishment of HIV latency reservoirs | PD-1, CTLA-4, LAG-3, TIGIT | Participate in HIV infection and assist to virus escape from immune clearance | [43,46,47,48,49] |
CD4+ T-cell dysfunction | PD-1, CTLA-4, LAG-3, TIM-3 | Cause many CD4 T-cells dysfunction and loss | [46,50,51,52,53] | |
CD8+ T-cell exhaustion | PD-1, TIM-3, LAG-3, TIGIT | Lead to CD8+ T-cell functional impact such as decreased IL-2 secretion and T-cell proliferation | [42,46,54,55] | |
Improved Treg proliferation | TIM-3, CTLA-4, PD-1 | Decrease the HIV-specific immune responses, contributing to virus persistence | [56,57,58,59] | |
HBV | CD8+ T-cell exhaustion | PD-1, CTLA-4, Tim-3, TIGIT, LAG-3 | Lead to CD8+ T-cell functional impact such as decreased IL-2 secretion and T-cell proliferation | [60,61,62,63] |
Upregulation on CD4+ T-cell | PD-1, CTLA-4, Tim-3 | Increase Treg and regulate Th1/Th2 cytokine secretion | [64,65,66,67] | |
Altered cytokine secretion | See Table 4 | See Table 4 | ||
Limited liver injury | LAG-3 | Suppress T-cell function and mitigate liver injury | [68] | |
HCV | CD8+ T-cell exhaustion | PD-1, TIGIT, Tim3, CTLA-4 | cause CD8+ T-cell functional defect such as decreased IL-2 secretion and T-cell proliferation | [69,70,71,72] |
Up-regulation on CD4+ T-cell | CTLA-4, TIM-3 | Improve viral replication and persistence | [67,73] | |
Altered cytokine secretion | See Table 4 | See Table 4 | ||
Influenza | Decrease in CD8+ T-cell response | PD-1, Tim-3 | Reduce the number of virus-specific CD8+ T-cell and cause T-cell dysfunction | [74,75,76,77,78,79,80,81,82] |
Up-regulation on both CD4+ and CD8+ T-cells from patients with influenza-associated encephalopathy | CTLA-4 | Involved in influenza virus-associated encephalopathy | ||
SARS-CoV-2 | Up-regulation on T-cells and NK cells from COVID-19 patients. Patient deteriorated from prodromal to symptomatic | PD-1, TIM-3 | Mediate T-cell exhaustion and T-cell lymphopenia | [83,84,85] |
HSV-1 | CD8+ T-cell exhaustion | PD-1, LAG-3 | Cause T-cell exhaustion and assist viral latency infection | [86,87,88] |
Reactivation of latency virus | PD-1, CTLA-4, TIM3 | Mediate T-cell exhaustion and make them lost the control of spontaneous HSV-1 reactivation | [89] | |
EBV | Up-regulated expression | PD-1, CTLA-4, TIM3, 2B4 | Provide T-cell dysfunction status to increase EBV escape and EBV latent infections | [90,91,92,93] |
Immune escape | PD-1 | |||
Ebola virus | Upregulation on both CD4+ and CD8+ T-cells; Associated with high viremia and poor outcome | CTLA-4, PD-1 | Mediate immune suppression | [94] |
3.2. The Upregulation of Immune Checkpoint Proteins Helps to Establish a Latent HIV Reservoir
4. Immune Checkpoints in Hepatitis Virus
4.1. Hepatitis Virus Infection Upregulates Immune Checkpoint Proteins on T-cells
4.2. Immune Checkpoints Affect Chronic Hepatitis Virus Infection through Cytokine Regulation
5. Immune Checkpoints in Influenza
6. Immune Checkpoints in COVID-19
7. Immune Checkpoints in Other Viruses
8. Summary and Outlook
Author Contributions
Funding
Conflicts of Interest
References
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Immune Checkpoint | Super Family | Ligand | Expression | T-cell Inactivation Pathway | Ref. |
---|---|---|---|---|---|
PD-1 | CD28 | PD-L1/L2 | T-cells, B-cells, natural killer T-cells, DCs and activated monocytes |
| [20,21,22] |
CTLA-4 | CD28 | B7 (CD80/CD86) | Active T-cells | CTLA-4 → PP2A → Akt → mTORc1 → regulates T-cell proliferation and differentiation | [25,26,27] |
TIM-3 | TIM | Galcetin-9 | Th1, Tc1, Treg cells |
| [32] |
TIGIT | CD28 | CD155 on DCs | T-cells and NK cells | TIGIT → SHIP1 → PI3K → AKT/PKC/IKK → NF-κB | [31,35] |
LAG-3 | Immunoglobulin | MHC class Ⅱ | Activated T-cells Treg cells, B-cells, DCs and NK cells | LAG- KIEELE motif /FXXL motif/ C terminus EX repeat → unknown | [38] |
BTLA/CD160 | CD28 | HVEM | T-cells and B-cells, activated T-cells |
| [39,41] |
Infection | Target | NCT ID | Research Title/Objective | Drug | Status |
---|---|---|---|---|---|
HIV | PD-1 | NCT03239899 | PD-1 Inhibition to Determine CNS Reservoir of HIV-Infection | Pembrolizumab | Phase Ⅰ |
PD-1 | NCT03787095 | Safety and Immunotherapeutic Activity of an Anti-PD-1 Antibody (Cemiplimab) in HIV-1-infected Participants on Suppressive cART | Cemiplimab | Phase Ⅰ | |
IMC | NCT03354936 | Assess the safety of the use of immune checkpoint inhibitors in HIV infected patients | Nivolumab, Pembrolizumab | Recruiting | |
PD-1 | NCT03367754 | A Single Dose of Pembrolizumab in HIV-Infected People | Pembrolizumab | Phase Ⅰ | |
HBV | PD-L1 | NCT03899428 | Immune Checkpoint Therapy vs Target Therapy in Reducing Serum HBsAg Levels in Patients with HBsAg+ Advanced Stage HCC | Durvalumab | Phase Ⅱ |
HCV | PD-1 | NCT00703469 | A Study of MDX-1106 to Treat Patients with Hepatitis C Infection (MDX1106-02) | MDX-1106 (PD-1 ab) | Phase Ⅰ |
Influenza | PD-1 | NCT03061955 | Safety and Efficacy of Concurrent Administration of Influenza Vaccine in Patients Undergoing Anti-PD-1 Immunotherapy (Nivolumab, Pembrolizumab) | Nivolumab, Pembrolizumab | Completed |
PD-1/CTLA-4 | NCT03590808 | Influenza Vaccination in Patients Receiving Immune Checkpoint Inhibitor | Pembrolizumab, Nivolumab, Ipilimumab | Completed | |
HPV | CTLA-4 | NCT01693783 | Ipilimumab in Treating Patients with Metastatic or Recurrent Human Papilloma Virus-Related Cervical Cancer | Ipilimumab | Phase Ⅱ |
EBV | PD-1 | NCT03755440 | PD-1 Antibody in EBV Positive Metastatic Gastric Cancer Patients | SHR-1210 (PD-1 ab) | Phase Ⅱ |
PD-1 | NCT02488759 | An Investigational Immuno-Therapy Study to Investigate the Safety and Effectiveness of Nivolumab, and Nivolumab Combination Therapy in Virus-associated Tumors (CheckMate358) | Nivolumab | Phase Ⅰ |
Chronic Virus | Cytokines Secretion during Viral Infection | Associated Immune Checkpoint | Effects | Ref. | |
---|---|---|---|---|---|
HBV | TH-1/CD8+T | IFN-γ ↓ | CTLA-4, PD-1, Tim-3, LAG-3, BTLA | Activate multiple immune responses Enhance Th1 responses Inhibit cccDNA replication and accumulation | [62,63,64,68,100,143,151,152,166] |
IL-2 ↓ | CTLA-4, BTLA, PD-1, Tim-3, LAG-3 | Induce differentiation and effector function of T-cell, NK and LAK | [62,64,67,143] | ||
TNF-α ↓ | PD-1, Tim-3, LAG-3 | Lead to direct clearance of virus-infection cells | [64,152,166] | ||
IL-12 ↓ | PD-1 | Impair host defense and viral clearance | [176] | ||
Treg | IL-10, TGF-β ↑ | CTLA-4, PD-1, Tim-3 | suppress effector T-cells and regulate liver fibrosis | [171,172,173] | |
TH-2 | IL-4, IL-5, IL-10 ↓ | LAG-3, PD-1 | Downregulate the activation of B- and T-cell proliferation Suppress TH1 response | [64] | |
TH-17 | IL-17 ↑ | TIM-3 | Promote the exacerbation of liver inflammation and sustain the proinflammatory response | [167] | |
HCV | TH-1/CD8+ T-cell | IFN-γ ↓ | LAG-3, PD-1, Tim-3 | Promote Th1 immune response, suppress Th2 and Th17 responses | [71,164] |
IL-2 ↓ | PD-1, CTLA-4 | Inactivate multiple immune-cell subsets, including T-cells, NK cells, B-cells, monocytes, macrophages, and neutrophils | [145] | ||
TNF-α ↓ | LAG-3 | Decrease the direct clearance of virus-infection cells | [164] | ||
IL-12 ↓ | Tim-3 | Decrease the stimulation of TH1 responses that are essential for host defense and pathogen clearance | [173] | ||
Treg | IL-10, TGF-β ↑ | PD-1, Tim-3, CTLA-4 | Limit the secretion of proinflammatory cytokines and suppress effector T-cells | [73,146,168] | |
TH-2 | IL-4, IL-5, IL-10 ↑ | PD-1 | Promote the activation of B and T-cell proliferation and limit the secretion of proinflammatory cytokines | [169] | |
TH-17 | IL-17 ↑ | Tim-3 | Promote the exacerbation of liver inflammation and injury | [173,174] |
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Cai, H.; Liu, G.; Zhong, J.; Zheng, K.; Xiao, H.; Li, C.; Song, X.; Li, Y.; Xu, C.; Wu, H.; et al. Immune Checkpoints in Viral Infections. Viruses 2020, 12, 1051. https://doi.org/10.3390/v12091051
Cai H, Liu G, Zhong J, Zheng K, Xiao H, Li C, Song X, Li Y, Xu C, Wu H, et al. Immune Checkpoints in Viral Infections. Viruses. 2020; 12(9):1051. https://doi.org/10.3390/v12091051
Chicago/Turabian StyleCai, Huiming, Ge Liu, Jianfeng Zhong, Kai Zheng, Haitao Xiao, Chenyang Li, Xun Song, Ying Li, Chenshu Xu, Haiqiang Wu, and et al. 2020. "Immune Checkpoints in Viral Infections" Viruses 12, no. 9: 1051. https://doi.org/10.3390/v12091051