A Focus on RNA Viruses

V iruses that use ribonucleic acid in their genetic material are generically referred to as RNA viruses. The lack of proofreading activity of viral RNA-dependent RNA polymerase can imbue these viruses with very high mutation rates, a feature that confers significant challenges for an infected host. Indeed, as a class, these viruses are responsible for a number of emerging and re-emerging diseases such as severe acute respiratory syndrome, acquired immune deficiency syndrome (AIDS), influenza, and hepatitis C. This issue of Viral Immunology features several papers that focus on recent advances in our understanding of the host response to several of these clinically important RNA viruses.

Influenza viruses have been very much in the public eye of late due to the emergence of pandemic strains. While much has been learned about influenza over the past decade, there is still much that we don't know about the inflammatory responses initiated by the virus and the nature of the pathogenesis mediated by different viral strains. To better understand the early virus-host interactions of pandemic influenza A viruses in humans, Patel and colleagues examined host responses to three 2009 H1N1 viruses. Infection of human epithelial cells with these viruses revealed significant differences in virus infectivity, interferon (IFN)-β levels, and the production of proinflammatory cytokines and chemokines. In a similar study, Tate and associates examined the capacity of virulent and avirulent strains of influenza A virus to infect mouse airway epithelial cells and alveolar macrophages. Interestingly, there were significant differences in the response of the epithelial cells and macrophages in terms of cytokine and chemokine production. The authors also noted differences in the capacity of different virus strains to mediate infection in the presence of C-type lectins, and argue that sensitivity to these lectins is a virulence factor. Together, the data from these studies offer insights into the mechanisms underlying disease severity following influenza virus infection. The pathogenesis of influenza virus infection may also be related to the nature of the initial inoculation. Smith and co-workers compared intranasal and aerosol routes of influenza virus inoculation in terms of immunity and disease pathogenesis in mice. The authors found that compared to intranasal inoculation, aerosol inoculation elicited more robust infection, characterized by enhanced morbidity, mortality, and pulmonary cell infiltration. These data offer a cautionary note about routes of infection for investigators utilizing mouse models of influenza. Another article in this issue addresses antibody responses to influenza virus. Varich and colleagues investigate whether antibodies can detect amino acid differences in relatively conserved influenza virus nucleoproteins. Two monoclonal antibodies were identified that distinguished human and avian influenza nucleoprotein strains and may be useful for differentiating these viruses.

Many other RNA viruses are associated with respiratory infections. A relative newcomer in this group is human metapneumovirus (hMPV), a negative single-stranded RNA virus that was first isolated in 2001 in the Netherlands. Although it is generally recognized as an important respiratory pathogen, only limited information is available on the relationship between hMPV and type I interferons. Scagnolari and associates have now examined this issue and show that hMPV is partially resistant to the antiviral activity of IFN-β and different IFN-α subtypes, relative to a well known IFN-sensitive virus, vesicular stomatitis virus. The authors note that additional studies are required to understand whether the relatively low sensitivity of hMPV to IFNs influences the clinical outcomes of infected individuals.

Another significant RNA virus is hepatitis C virus, which has infected upwards of 270–300 million people worldwide. The virus causes liver cirrhosis, liver failure, and liver cancer. There is currently no vaccine against this clinically important infection. Using a multi-step bioinformatics approach, Vasiljevic and co-workers show that natural autoantibodies from healthy blood donors gave positive responses in commercial anti-HCV screening assays. These data suggest approaches for reducing false-positives in HCV screening assays. With respect to vaccine development against HCV, Yang and colleagues show that a synthetic multi-epitope antigen is highly immunogenic in mice, eliciting both humoral and cellular immune responses. While this may be a step towards vaccine development, there are many challenges ahead. Ayers and associates evaluated the state of B cells during chronic HCV infection, and observed a diminished ability to respond to mitogenic stimuli, correlating with increased apoptosis. Interestingly, HCV-exposed B cells also showed an enhanced ability to generate regulatory T cells (Tregs), and provide a paradoxical link between HCV-induced enhanced antigen-presenting cell function and the generation of Tregs.

The last RNA virus addressed in this issue is the human immunodeficiency virus (HIV) responsible for most cases of AIDS. Chung and colleagues studied antibody-dependent cellular cytotoxicity (ADCC) antibodies in the serum of individuals with early HIV infection. Their data suggest that HIV-specific ADCC responses to conformational epitopes occur early during acute HIV infection and broaden to include linear epitopes over time. These findings have implications for the immune control of HIV.

Other articles in this issue focus on a completely different set of viruses that use DNA in their genetic material, specifically the herpes viruses. Petersen and associates identify T-cell markers of reactivation of human cytomegalovirus in chronic lymphocytic leukemia patients, and suggest that they can be used as early predictors of reactivation. Nagata and co-workers study the influence of Epstein-Barr virus reactivation in patients with Graves' disease. And finally, Ogunjimi and colleagues investigate the impact of exposure to primary varicella in children on varicella-zoster virus immunity of parents.