Epstein–Barr Virus and Grave's Disease

Epstein–Barr virus (EBV) is a persistent herpesvirus that is transmitted primarily through bodily fluids, such as saliva. Most people become infected with EBV at some point in their lives, and infection later in life is sometimes associated with EBV-mediated infectious mononucleosis and other illnesses. In the current issue of Viral Immunology, Nagata et al. discuss EBV reactivation-induced immunoglobulin production and immunoglobulin G4-related disease (IgG4-RD), a newly recognized systemic fibroinflammatory disease with characteristic histological findings and high serum IgG4 levels. The authors had previously shown that EBV reactivation induced the production of thyrotropin receptor antibodies, the causative antibodies of Graves' disease. They investigated EBV reactivation-induced IgG4 production and whether EBV-positive B cells or IgG4-positive plasma cells are present in the thyroid tissues of Graves' disease patients with lymphoplasmacytic infiltration. Their data show that a subset of Graves' disease is an IgG4-RD-like condition, but not a bona fide IgG4-RD.

Two articles in the current issue of Viral Immunology focus on regulatory T cells. Wei et al. note that direct-acting antivirals (DAAs) not only rapidly inhibit hepatitis C virus (HCV) replication but also modulate innate and adaptive immune responses in chronic hepatitis C patients. However, the regulatory activity of DAAs on regulatory T cells (Tregs) and T helper (Th) 17 cells is not understood. Here, the authors show that inhibition of HCV RNA by daclatasvir and asunaprevir did not affect either the percentage of Tregs and Th17 cells or the expression of Toll-like receptor-2 on these cells. Rather, these data suggested that daclatasvir plus asunaprevir therapy resulted in the decreased responsiveness of Tregs and Th17 cells to Toll-like receptor-2 stimulation in chronic hepatitis C patients. Thus, the effect is on function and not number of cells and highlights a novel mechanism of DAAs-induced immunoregulation. Shen and colleagues note that regulatory T cells increase in hepatitis B virus (HBV) infection, but their role in the progression of HBV infection is not understood. In this study, the authors show that CD28⁺CD8⁻ and CD4⁺CD25 high regulatory T cells exert distinct effects on the antiviral immune responses. These cells also mitigate immune-mediated liver damage in different phases of HBV infection. These cell subsets are potential prognostic markers and therapeutic targets for HBV-infected patients.

The innate response to viral infections is also extensively investigated in the current issue of Viral immunology. Jamhiri et al. have studied the role of HCV nonstructural protein 3 in the induction of fibrotic disease. The authors not only confirm the inflammatory and fibrotic effect of this protein but also show that high expression of suppressor of cytokine signaling-1, -3, and interleukin-24 has a significant effect on hepatic stellate cell activation. These molecules are potential therapeutic target candidates. Kumar and colleagues have evaluated the role of two different forms of vitamin D: 25-hydroxyvitamin D3 (25D3) and 1,25-dihydroxyvitamin D3 (1,25D3) against herpes simplex virus-1 (HSV-1) in Hela cells. The supplementation of both 25D3 and 1.25D3 before HSV-1 infection was found to downregulate the viral titer and Toll-like receptor-2 messenger RNA levels during the initial phase of infection. In addition, the effect of 25D3 supplementation lasted significantly longer than that of 1.25D3. In another article, Ferreira and colleagues point out that microRNAs (miRNAs) interfere with different stages of the replicative cycle of several viruses and may influence the disease outcome. To better understand this in the context of Zika virus (ZIKV) infection, the authors have investigated ZIKV-induced regulation of host miRNA-processing machinery. Their studies focused on the expression of genes encoding key proteins of the miRNA pathway in different ZIKV-infected primate cell lineages. The data show that ZIKV modulates miRNA levels during infection in liver, lung, and kidney cells, and may represent an important mechanism of host cell subversion in these organs.

Viral diagnostics are also discussed in the current issue of Viral Immunology. Acute HCV infection is usually asymptomatic and can remain undiagnosed in individuals who progress to chronic infection. Consequently, the first signs of infection may only emerge after serious liver damage has developed. Gauna et al. report on the development of a diagnostic assay using a conserved 20-mer linear peptide belonging to the N-terminus of the viral core protein as a target antigen. Diagnostic studies with this antigen showed 100% sensitivity and specificity in 22 patient samples. The authors note that the approach they used to identify the target antigen in this case could be used for many other viruses for the development of rapid, integrated, and inexpensive diagnostics.

I would like to thank all of the authors for their excellent contributions to this issue of the Journal and all of the reviewers who work tirelessly to ensure the high quality of accepted articles.