New Approaches for the Control of Influenza

A s in previous years, we enter the 2011–2012 influenza season with inadequate tools to fight this dangerous virus. The emergence of drug-resistant virus strains, the persistence of the highly pathogenic H5N1 (bird flu) virus, and the ever-present threat of new pandemic strains, continue to cause concern in the medical community. There is no question that we desperately need improved vaccines and therapeutics. This issue of Viral Immunology contains several strong articles that offer new insights into the influenza-host relationship that might lead to novel approaches to the control of influenza. Rogers and colleagues have characterized microRNA (miRNA) expression in lung tissue from mice infected with an H5N1 virus. Many of the expression patterns mapped to common biological functions, and one of the miRNA-specific predicted genes identified throughout infection was furin (a subtilisin-like proteinase and therapeutic drug target). These data advance our understanding of differential miRNA expression with respect to the host-pathogen relationship, and potentially identify therapeutic drug targets. In another study, Munir and associates analyzed alleles of the non-structural protein 1 (NS1) of influenza virus. NS1 antagonizes the host immune response by interfering in several host signaling pathways. In their article, the authors show that NS1 alleles from avian influenza A viruses differ in their ability to inhibit the double stranded (dsRNA)-induced activating protein-1 (AP-1) promoter in cultured cell lines. Further studies on the molecular mechanism behind this differential inhibition may advance our understanding of the zoonotic and pathogenic potential of influenza A viruses. For example, aberrant systemic inflammation is frequently induced by influenza A virus infection, and the severity of the symptoms is associated with pathogenicity of the virus. In this regard, Kondoh and colleagues have investigated whether the anti-inflammatory properties of a lactic acid bacteria strain, Enterococcus faecalis FK-23, are able to reduce the severity of influenza virus infections. The data show that oral administration of water-soluble and heat-treated FK-23 preparations to mice increased the expression of the anti-inflammatory cytokine interleukin-10, and resulted in enhanced survival of the mice following influenza virus infection. Together, these three reports considerably advance our understanding of the interplay between the influenza virus and the host, and suggest new strategies to control influenza infections in general.

The interplay between the host and virus is a common feature of infections mediated by many types of viruses. One of the most prominent examples is the interplay between human immunodeficiency virus-1 (HIV-1) and the infected individual. Highly-active antiretroviral therapy can drive down the viral load and boost T-cell immunity, even in the presence of multidrug-resistant viruses. Sharma and colleagues compared the replication capacity and the expression of anti-apoptosis marker genes in human peripheral blood mononuclear cells infected with wild-type and mutant viruses. The authors showed that the expression of specific anti-apoptosis marker genes was upregulated in mutated viruses (relative to wild-type virus), and that the expression of these genes was independent of the replication capacity of the viruses. These data suggest that multidrug resistant viruses may protect infected CD4⁺ T cells from death. Another clinically significant virus that illustrates host/virus interactions is the hepatitis B virus (HBV), which causes chronic hepatitis. Nan and colleagues have investigated the mechanism by which the nucleotide analogue telbivudine works. They show that the antiviral effect of the nucleoside analog may be attributed not only to its direct effect on virus suppression, but also by reducing regulatory T cells, and thereby enhancing the immune response to the virus. These data have important implications for the treatment of this very significant clinical problem.

Several articles in this issue focus on vaccine development. Umlauf and colleagues have analyzed the relationship between various demographic variables and several measles-specific innate and cell-mediated immune responses following measles vaccination. Their data suggest that immune responses to measles vaccine vary significantly by gender and race, and advance our understanding of subgroup variation and measles vaccination. The effects of a therapeutic dendritic cell-based vaccine against HIV-1 infection have been investigated by Peña and colleagues. Their study indicates that this vaccine might enhance innate immunity by amplifying both inflammation and natural killer cell cytolytic capacity. Another study involving a dendritic cell-based vaccine for HIV-1 shows that this type of vaccine is capable of eliciting potent poly-functional T-cell responses in vitro. Kurle and associates suggest that their in vitro approach may be used to assess the probable immune response against a candidate vaccine.

Vaccine development is not exclusively focused on the human population. Two articles in this issue address the challenges associated with the development of livestock vaccines. Gnazzo and colleagues have developed a live attenuated Salmonella typhimurium vaccine that delivers tandem copies of an immunogenic peptide of bovine herpes virus-1 (BoHV-1) glycoprotein D. Intranasal delivery of the vaccine induced specific humoral and cellular immune responses against the selected peptides, and this response cross-reacted with intact glycoprotein D and whole BoHV-1 virus. This is the first time Salmonella has been used as an expression vector to induce immunity against BoHV-1. Meir and colleagues have evaluated vaccine strategies for infectious bronchitis virus, a highly contagious, acute viral disease of the upper respiratory tract in chickens. The authors show that recombinant viral proteins administered through the mucosal route can evoke an immune response without the assistance of a vector. This finding has important applications for the development of subunit vaccines to other pathogens.

One article in this issue addresses the immunogenetics of virus infection. Song and colleagues note that host genetics play a central role in determining clinical outcomes of HBV infection. In this regard, the tumor necrosis factor receptor-associated factor family member-associated NF-κB activator (TANK) is involved in both the TNF-α-mediated NF-κB signaling pathway and the IFN induction pathways, both of which have relevance to HBV-related liver disease. The authors demonstrate that polymorphisms in the TANK gene are protective against susceptibility to acute-on-chronic hepatitis B liver failure and liver cirrhosis in the Chinese Han population. The authors note that these studies need to be extended to other populations to further explore the role of TANK in the progression of HBV infection.

Finally, I would like to take this opportunity to thank all of the reviewers that have donated their time and energy to review manuscripts for Viral Immunology. Stringent peer review by our volunteer reviewers is essential to maintain the quality of the work showcased in this journal. The efforts of all of our reviewers are deeply appreciated by me, the staff of Viral Immunology, and all of our readers.