Regulatory T Cells and Influenza

Regulatory T cells (Treg) play a central role in calibrating immune responses and helping establish tolerance to self-antigens. Tregs function by suppressing the activity of other immune cells. However, we have only a rudimentary understanding of the underlying mechanisms of action in the context of infection. In this regard, Oliphant and colleagues have addressed the role of Tregs in regulating the immune response to influenza A virus infection. The authors had previously reported that neonatal mice infected with influenza A virus develop interstitial pneumonia characterized by reduced lung cytokine and chemokine responses and delayed clearance of virus compared to adults. They hypothesized that Tregs are responsible for this difference. Indeed, analysis of mice that had defective Treg responses had increased lung T-cell responses, but significantly elevated viral loads compared to controls. The authors conclude that Tregs are critical for clearance of influenza virus in neonatal mice.

Two additional articles in this issue of Viral Immunology address other aspects of influenza A virus infections. Lohia and colleagues have used an immunoinformatics-based consensus approach for epitope prediction to identify T-cell peptide epitopes, using conserved sequences from Matrix 1 protein sequences. They identified three CD4+ and CD8+ T-cell epitopes that are highly conserved across many subtypes of influenza virus that infect humans. Binding studies of the predicted peptides with class I and II human leukocyte antigen (HLA) molecules further indicated that the majority of them exhibited strong binding energies, making them promising candidates for the development of universal influenza vaccines. Yum et al. noted that the H7N9 influenza virus has been infecting humans in China since February 2013 and causes about 40% mortality. In their current study, they compare the pathogenicity of the H7N9 and 2009 pandemic H1N1 influenza viruses in a ferret model, which shows similar symptoms to those of humans infected with influenza viruses. The data indicate that the H7N9 influenza virus grew to higher viral titers in the ferrets' lungs than the 2009 pandemic H1N1 influenza virus and also induced hemorrhagic pneumonia. These findings reinforce the view that close monitoring is needed to prevent human infection by the lethal H7N9 influenza virus.

The remaining articles in this issue concern a variety of important viruses. A review by Desai et al. investigates the relationship between herpes simplex virus (HSV) and human immunodeficiency virus (HIV). The authors point out that HSV proteins interact with host (human) proteins and create an environment conducive for its replication. Genital ulceration due to herpes simplex virus type 2 (HSV-2) infections is an important clinical manifestation reported to increase the risk of HIV-1 acquisition and replication in HIV-1/HSV-2 coinfection. Their article reviews studies on the influence of HSV-derived proteins on the host response and HIV-1 replication with a view to designing and developing common strategies for the control of coinfections. Enteroviruses have been suggested as triggers of type 1 diabetes, but direct evidence has been lacking. To further investigate this issue, Witsø et al. have analyzed type 1 diabetes susceptibility single-nucleotide polymorphisms (SNPs) and candidate SNPs in innate immune genes to determine whether they are associated with the frequency of enteroviruses infection in otherwise healthy Norwegian children. Among a number of SNPs in candidate genes, the authors found no evidence for strong associations with enterovirus presence in stool samples. Valere and colleagues note that alpha-defensins, including human neutrophil peptides 1–3 (HNP1-3), are elevated at the genital mucosa in individuals with sexually transmitted infections. In this study, they show that HNP1 increases HIV traversal of the epithelial barrier, suggesting a potential role in sexually transmitted infection-mediated enhancement of HIV transmission. Porcine circovirus type 2 (PCV2) is associated with a number of diseases and syndromes, collectively referred to as porcine circovirus-associated disease. Zanotti and colleagues have analyzed in vitro correlates of protection following injection of inactivated PCV2 vaccines and demonstrate that cell-mediated immune parameters showed a good correlation with vaccine efficacy. In particular, the interferon-γ release assay was an effective marker for predicting protection. The study identifies in vitro testing procedures that can be used to reduce animal usage in the control of PCV2 vaccine batches.

Last but not least, an interesting study by Lake-Bakaar and colleagues investigates the impact of controlled therapy interruption on immune control of hepatitis B virus (HBV) infection in chronically infected patients. The authors initiated transient treatment interruptions during otherwise continuous oral antiviral therapy, which allows bursts of viremia, simulating autovaccination. The data indicate that patients have low baseline levels of host immune control against HBV, but that controlled therapy interruption consistently boosted this immunity.

Once again, I would like to thank all of the authors for their excellent contributions to this issue of the journal and all of the reviewers for their efforts to quality control the articles published.