Advances in Flavivirus Research

A major feature of this issue of Viral Immunology is a brace of papers on flaviviruses. The flaviviruses are single-stranded positive-sense RNA genome viruses that are transmitted by mosquitoes and ticks. They include many human pathogens, such as dengue virus (DENV) and yellow fever virus (YFV), and are responsible for a significant amount of morbidity and mortality worldwide. Recently, the National Institute of Allergy and Infectious Diseases (NIAID) convened a workshop to discuss progress in identifying flavivirus T- and B-cell epitopes. The goal was to determine how this information could be used to understand host-pathogen interactions and develop new vaccines and diagnostics. Here, Augustine and Repika report on the workshop and outline the ideas and approaches that were proposed for future research efforts in this area. One key proposal was that T- and B-cell epitopes be identified in flaviviruses for which molecular structures or amino acid sequences have not yet been defined. In this regard, the NIAID supports the Immune Epitope Database and Analysis Resource (IEDB) to provide scientists with immune epitope information for infectious and immune-mediated diseases. Due to the clinical significance of flaviviruses, the NIAID suggested that the IEDB staff conduct a meta-analysis of flavivirus immune epitopes. This meta-analysis is now published in this issue of Viral Immunology. Vaughan and Sette report on 2000 epitopes from over 130 individual flavivirus-related references identified in PubMed and curated into the IEDB. The report notes that the majority of the described epitopes were from DENV and West Nile virus, presumably because of their impact on human disease, and the lack of vaccines. This important report will be an invaluable tool for Flavivirus researchers.

Two papers in this issue focus on innate immune responses. Singh and colleagues discuss the role of plasmacytoid dendritic cells (pDCs) during early human immunodeficiency virus (HIV) infection. The authors show that the pDC population upregulated apoptotic markers in recent and advanced HIV infection, and suggest that apoptotic loss of pDCs may be responsible for impaired innate anti-HIV immune responses. Interestingly, the presence of functionally-competent pDCs in slow progressors implies that these cells influence the progression of disease. He and colleagues discuss the role of IFNAR1 genetic polymorphisms on the long-term pathogenesis of chronic hepatitis B virus (HBV) infection. The data suggest that the genetic IFNAR1 contributes both to clearance and chronicity at the early stage of HBV exposure, and persistently influences pathogenesis during long-term chronic infection.

The relationship between the innate and adaptive immune responses is complex and involves several levels of regulatory interplay. The transcription factor NF-κB plays a key role in regulating both responses through two major signaling pathways. Signaling through the classical NF-κB pathway usually results in the nuclear translocation of RelA/p50 dimers and regulation of the innate immune response. In contrast the alternative NF-κB signaling pathway involves the RelB/p52 subunits, and results in the regulation of the adaptive immune response. Planz and colleagues have now investigated the roles of these pathways in the immune control of lymphocytic choriomeningitis virus (LCMV). Using mice that are deficient in NF-κB subunits from either the classical (p50^−/−) or the alternative NF-κB pathway (p52^−/−), the authors show that the alternative NF-κB pathway is required for the T-cell-mediated immune response against LCMV. Furthermore, the requirement for the alternative NF-κB pathway was manifest at the level of T-cell priming. Von Herrath and colleagues have analyzed the T-cell response to LCMV in the context of chronic infection. The authors note that chronic infections of this nature are often associated with impaired antiviral CD8 and CD4 T-cell responses. In addition, they found that CD103, an alpha E integrin necessary for T-cell homing and retention in the gut and other epithelia, was upregulated on regulatory T cells (Tregs) during chronic LCMV infection. However, further analysis revealed that CD103 expression on Tregs in chronically-infected mice does not significantly contribute to T-cell exhaustion. To further understand immune responses to viral infection, Heidari and colleagues have conducted a global host gene expression analysis of the chicken response to Marek's disease virus (MDV). The study analyzed more than 32,000 chicken transcripts and most of the known MDV genes and open reading frames during MDV infection. The study identified a number of immune-related genes with altered expression levels during infection, and the data should be invaluable for better understanding the host response to this virus.

Highly pathogenic H5N1 influenza viruses continue to be reported, raising concerns that this virus could trigger a pandemic sometime in the near future. Two articles focus on the development of vaccines against highly pathogenic H5N1 influenza viruses. Using a ferret model, Shin and colleagues assessed the efficacy of an inactivated H5N1 vaccine in terms of immune responses and protection from death. The data suggest that IgG antibodies elicited by the vaccine may play a major role in protecting ferrets from lethal H5N1 influenza virus challenge. Kositanont and colleagues make the important observation that cross-neutralizing antibody against H5N1 virus can be induced after vaccination with seasonal influenza vaccine. These data suggest that influenza vaccination, but not influenza virus infection, could induce cross-neutralizing antibody against avian influenza H5N1 virus.

Also on the vaccine front, Al-Mahtab and colleagues investigate approaches to control chronic HBV infections in carriers that are at risk of developing liver disease. While antiviral drugs are not effective or recommended for treatment of these patients, the authors postulate that a combination therapy of an HBV vaccine and antiviral drugs may be more effective. Indeed, combination therapy appeared to be safe, possibly protected against liver damage, and reduced HBV DNA levels in all patients. This combination therapy may be a viable option for the control of HBV in asymptomatic chronic HBV carriers.