An Update on Hantaviruses

Hantaviruses are single-stranded, negative-sense RNA viruses that typically infect rodents, but which can also infect humans. Infection of humans with some strains of hantavirus can result in hemorrhagic fever with renal syndrome (HFRS), or pulmonary syndrome, both of which can be fatal. Relatively little is known about the virus and the associated pathogenesis. However, two papers in this issue of Viral Immunology address key issues about the host response to hantavirus infection. First, Tang et al. have investigated the role of CD14 in hantavirus infection. The authors note that CD14, a pattern recognition receptor recognizing lipopolysaccharide, is highly expressed on monocytes, and can be shed as soluble CD14 upon monocyte activation. To understand the role of soluble CD14 in HFRS, the authors analyzed the soluble CD14 plasma concentrations from 45 HFRS patients. Interestingly, plasma-soluble CD14 levels were significantly higher in HFRS patients and correlated with monocyte expansion and activation, elevated plasma tumor necrosis factor-α levels, and altered platelet counts, indicating that elevated plasma-soluble CD14 levels are associated with the monocyte response status during hantavirus infection in humans. Second, Pan et al. have investigated the effect of hantavirus nucleocapsid protein on the regulation of the interferon (IFN) pathway with a view to understanding its role in regulating human's innate antiviral immune response to the virus. The authors report that the nucleocapsid protein significantly inhibits IFN-β production at high doses. The data suggest that the suppression of host antiviral responses plays a key role in allowing the virus to establish infection effectively. Further support for this idea came from the observation that a high dose of hantavirus nucleocapsid protein could inhibit vesicular stomatitis virus-induced IFN-β production and the activation of IFN-stimulated genes.

The immune system is a highly regulated and finely tuned system that is designed to ignore self-antigens while targeting foreign antigens on pathogens. One of the immune cell types that mediates this regulation is the regulatory T cell (Treg), or suppressor cell. However, the role of these cells in chronic infections and their potential as targets for therapeutics is poorly understood. This question has been addressed by Feng et al., who have analyzed the Treg response in patients during the progression of chronic hepatitis B virus (HBV) infection. The authors focus on programmed death ligand-1 (PD-L1), which is expressed on Tregs and can transduce an inhibitory signal into effector T cells through interacting with programmed death-1 (PD-1). Their data indicate that both the frequency of Tregs and PD-L1 expression on Tregs in the peripheral blood of chronically HBV-infected patients were significantly higher than in healthy controls. Furthermore, both Treg frequency and PD-L1 expression on Tregs positively correlated with the levels of alanine aminotransaminase and aspartate aminotransferase, both of which are indicators of the extent of liver injury. These data support the idea that blockade of PD-L1 and PD-1 interactions may be a therapeutic approach to control chronic HBV infection by removing one of the suppressive mechanisms that stop the immune system from clearing the virus. Along the same lines, Feng et al. have analyzed Treg and Th17 cell numbers during antiviral treatment in chronic HBV patients. The numbers of both types of cells were increased in the infected patients compared with healthy adults, but were decreased in individuals undergoing IFN-α treatment to suppress viral replication. The authors argue that Treg and Th17 cells might be important factors during IFN-α treatment of chronic HBV infection.

Another chronic infection of considerable clinical significance is that mediated by the human immunodeficiency virus (HIV). As with chronic HBV infection, there are signs of T cell dysfunction or exhaustion during HIV infection, especially in the HIV-specific CD8+ T cell pool. Adegoke et al. point out that the HIV-specific CD8+ T cells of some individuals cross-react with certain peptide epitope variants and produce enhanced levels of cytokine relative to stimulation with the native peptides. They go on to determine whether peptide variants that enhance cytokine production by HIV-specific CD8+ T cells also reduce functional and phenotypic evidence of HIV-specific CD8+ T cell exhaustion. Analysis of 24 variant peptides revealed that HIV-specific CD8+ T cells proliferated more rapidly and expressed lower levels of PD1 than in response to the native peptide. The data demonstrate that variant peptides can alter the magnitude and character of HIV-specific CD8+ T cell responses and may have value in therapeutic vaccines.

Four additional papers in this issue of Viral Immunology address different aspects of the host response to viral infection. Golsaz-Shirazi et al. have examined variable region genes of immunoglobulin heavy and light chains of antibodies specific for HBV surface antigen. The authors identify heavy and light chains that are preferentially used to generate anti-HBV surface antigen antibodies. Świątek-Kościelna et al. have focused on another virus that can cause chronic infections—hepatitis C virus (HCV). The authors show that HCV infection and IFN-based treatment induce p53 gene transcription and presumably regulate viral replication at some level. Chaudhary et al. have analyzed the impact of dendritic cell-specific intracellular adhesion molecule 3 grabbing non-integrin related molecule (DC-SIGNR) genotypes on HIV infection. The authors find that one genotype of DC-SIGNR is associated with low DC-SIGNR expression and high CD4+ T cell counts, suggesting a protective role in HIV-1 infection. Finally, Papatsiros et al. describe an erythema multiforme (EM) associated with a respiratory disease in a commercial breeding pig herd. The authors conclude that the EM was likely due to illness caused by viral and bacterial infections and that stress in the herd might have triggered the problem.

Finally, I would like to thank all of the authors for their excellent contributions to this issue of Viral Immunology and all of the reviewers that help to maintain the quality of the articles published in the journal.