Viral Immunology

Tumor necrosis factor superfamily 14 (TNFSF14) (LIGHT) is an interesting costimulatory molecule associated with T lymphocyte activation, and it mainly exerts its biological effects by binding to its receptors herpesvirus invasion mediator (HVEM) and lymphotoxin-β receptor. Research shows that TNFSF14 plays a critical regulatory role in immune responses to viral infection, but its role is different in different diseases. TNFSF14 can be a cytokine neutralization target during novel coronavirus infection, and anti-TNFSF14 monoclonal antibody treatment can reduce the risk of respiratory failure and mortality. When the host is infected with adenovirus, TNFSF14 can be used as an inflammatory biomarker to indicate whether there was an adenovirus infection in the host and the degree of disease caused by viral infection. When hosts suffer influenza virus infection, the TNFSF14-HVEM signaling pathway can stimulate the maturation and proliferation of memory CD8⁺ T cells, which helps the host immune system stimulate a second immune response against respiratory virus infection. TNFSF14 can act as an immune adjuvant and enhance the immunogenicity of the human papillomavirus (HPV) DNA vaccine when the host is infected with HPV. During hepatitis virus infection, TNFSF14 acts as a proinflammatory factor, participates in inflammation and causes tissue damage. In conclusion, TNFSF14 plays different and significant roles in diverse viral infections. This article reviews the current research on TNFSF14 in antiviral immunity.

Infection caused by the Zika virus (ZIKV) can lead to serious neurological complications such as microcephaly in neonates. At present, no approved ZIKV vaccine is available, but few vaccine candidates are undergoing clinical trial. One major challenge faced is antibody-dependent enhancement (ADE) reaction that may provoke severe outcome in subsequent infection by ZIKV or other flaviviruses. Thus, more efforts should be dedicated to understanding ADE in designing a safe and effective vaccine to minimize the consequence of the potentially fatal infection's complications and to tackle potential ZIKV reemergence. This review discusses different types of ZIKV vaccine candidates that are currently underway in various stages of preclinical and clinical evaluations.

Several studies have reported that hepatitis B virus (HBV) infection is mediated by macrophages and that the B7x (B7-H4, VTCN-1) protein plays an important role in immune regulation in HBV-associated hepatocellular carcinoma (HBV-HCC). However, the relationship among HBV, macrophages, and B7x has not been studied. In this study, HBV-infected mouse model and coculture of HBV cell lines and macrophages were used to observe the changes in macrophages and the role of B7x after HBV infection. The expression of HBV markers (HBeAg, HBsAg), negative regulator of immunity (B7x), T-helper 17 (Th17)/T-regulatory (Treg)-related cytokines, and macrophage markers, as well as changes in the apoptosis and cell cycle of macrophages were analyzed through reverse transcription quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, western blot, and flow cytometry. The expression of HBsAg, HBeAg, and B7x increased and the levels of macrophage surface marker and Treg cells secrete related cytokines (IL-10 and TGF-β) were altered after HBV infection both in vivo and in vitro. Apoptosis of macrophages increased, and cell cycle arrest occurred in vitro. These effects, except those in the cell cycle, were reversed when B7x was knocked down. Thus, HBV infection can promote the expression of B7x, which in turn regulates the Th17/Treg balance and affects the expression of HBsAg and HBeAg. The mechanism used by B7x likely involves the promotion of macrophage polarization and apoptosis. These results suggest that B7x is a novel target for HBV immunotherapy.

Host genetic factors could play a primary role in determining the risk for cirrhosis development in chronic hepatitis C virus (HCV)-infected patients. We designed this work to study the effect of single-nucleotide polymorphism (SNP) in Toll-like receptor 3 (TLR3) and interferon regulatory factor (IRF) on the risk of HCV-related cirrhosis. This study enrolled 139 Egyptian HCV-infected patients. They were divided into patients with cirrhotic (56) and noncirrhotic (83) liver. Genotyping of rs3775291 F459F (+1234C/T) and rs3775290 L412F (+1377C/T) in TLR3 and IRF3 rs2304204 (−925A/G) was performed by restriction fragment length polymorphism–polymerase chain reaction. Although there is no significant difference in genotype and allele distribution of +1377C/T of TLR3 gene between cirrhotic and noncirrhotic subjects, CC (odds ratio [OR] = 1.572, 95% confidence interval [CI]: 0.781–3.164); TT (OR = 1.463, 95% CI: 0.351–6.104) genotypes might be considered as risk factors for liver cirrhosis. On the contrary, the analysis revealed that only one genotype (CC) and one allele (C) were detected in +1234C/T SNP, with the total disappearance of CT/TT genotypes and T allele in all subjects. On the contrary, lower frequency has been found for the AG genotype of the IRF3 (−925A/G) gene in cirrhotic patients compared with noncirrhotic ones, indicating that AG is a protective genotype (OR = 0.509, 95% CI: 0.256–1.012). Our data stressed the association of AG genotype SNP in IRF3 (−925A/G) in protection against the worth outcome of HCV infection.

Dendritic cells (DCs), as the most powerful antigen-presenting cells, play a key role in the adaptive immune response, while the defective function of DC is an important factor in immune tolerance to hepatitis B virus (HBV) infection. Hepatitis B virus core antigen (HBcAg) is a highly antigenic protein that can induce a strong antigen-specific immune response against HBV. In this study, we first constructed the ubiquitinated HBcAg gene (UbHBcAg), and then utilized a recombinant lentiviral vector UbHBcAg (LV-UbHBcAg) to explore the role of them in DC autophagy and function. Meanwhile, the effects of autophagy on DC functional activation were further analyzed. Finally, we investigated the underlying mechanism of autophagy induced by LV-UbHBcAg. Results showed that LV-UbHBcAg could promote autophagic progression in DCs, and the upregulated autophagy can further enhance DC functional maturation. In addition, p62 may serve as an important role in autophagy degradation. More importantly, the PI3K/Akt/mTOR signaling pathway was involved in the process of autophagy induced by LV-UbHBcAg. These findings suggest that LV-UbHBcAg can activate DC function by inducing autophagy, which may represent a promising strategy to treat chronic HBV infection.