Towards the Application of Human Defensins as Antivirals

Defensins are antimicrobial peptides that participate in the innate immunity of hosts. Humans constitutively and/or inducibly express α- and β-defensins, which are known for their antiviral and antibacterial activities. This review describes the application of human defensins. We discuss the extant experimental results, limited though they are, to consider the potential applicability of human defensins as antiviral agents. Given their antiviral effects, we propose that basic research be conducted on human defensins that focuses on RNA viruses, such as human immunodeficiency virus (HIV), influenza A virus (IAV), respiratory syncytial virus (RSV), and dengue virus (DENV), which are considered serious human pathogens but have posed huge challenges for vaccine development for different reasons. Concerning the prophylactic and therapeutic applications of defensins, we then discuss the applicability of human defensins as antivirals that has been demonstrated in reports using animal models. Finally, we discuss the potential adjuvant-like activity of human defensins and propose an exploration of the ‘defensin vaccine’ concept to prime the body with a controlled supply of human defensins. In sum, we suggest a conceptual framework to achieve the practical application of human defensins to combat viral infections.

Original Antigenic Sin Response to RNA Viruses and Antiviral Immunity

The human immune system has evolved to fight against foreign pathogens. It plays a central role in the body's defense mechanism. However, the immune memory geared to fight off a previously recognized pathogen, tends to remember an original form of the pathogen when a variant form subsequently invades. This has been termed 'original antigenic sin'. This adverse immunological effect can alter vaccine effectiveness and sometimes cause enhanced pathogenicity or additional inflammatory responses, according to the type of pathogen and the circumstances of infection. Here we aim to give a simplified conceptual understanding of virus infection and original antigenic sin by comparing and contrasting the two examples of recurring infections such as influenza and dengue viruses in humans.

Original Antigenic Sin Response to RNA Viruses and Antiviral Immunity

The human immune system has evolved to fight against foreign pathogens. It plays a central role in the body's defense mechanism. However, the immune memory geared to fight off a previously recognized pathogen, tends to remember an original form of the pathogen when a variant form subsequently invades. This has been termed 'original antigenic sin'. This adverse immunological effect can alter vaccine effectiveness and sometimes cause enhanced pathogenicity or additional inflammatory responses, according to the type of pathogen and the circumstances of infection. Here we aim to give a simplified conceptual understanding of virus infection and original antigenic sin by comparing and contrasting the two examples of recurring infections such as influenza and dengue viruses in humans.

Strategy for Developing Medical Arsenals by Modulation of Membrane Fusion Activity of Influenza Virus Hemagglutinin

Influenza virus is a serious pathogen that burdens society with health care costs, and can lead to fatality. The virus is dealt with currently by vaccination and anti-influenza drugs. However, vaccines need to be improved towards safer and more efficient production formats, and drugs need to be constantly renewed to cope with resistances. That the neuraminidase inhibitors are only drugs currently available warrants urgent attention to an alternative anti-influenza target. In this paper we introduce studies on fusion activity of influenza virus hemagglutinin (HA), and discuss how to best utilize the knowledge for an improved vaccine development and an anti-influenza drug search. Potential application of mutations resulting in changes in fusion activity to cell culture optimized vaccine virus development and strategies to develop broad spectrum anti-influenza drugs through targeting the conserved fusion domain of the HA are discussed.

Cell Culture-based Influenza Vaccines as Alternatives to Egg-based Vaccines

Influenza viruses have raised public health concerns by seasonal epidemics and intermittent pandemics. Vaccination is considered as the most effective method for preventing influenza infection in humans. Current influenza vaccines are mostly produced in fertile chicken eggs. However, disadvantages of egg-based vaccines, such as egg dependency, labor-intensive manufacturing system, and huddle for large-scale output, allow us to make an alternative method. A cell-culture platform may be a fine alternative for the next generation vaccine technique. Compared with a classical egg-based method, cell-grown vaccines provide stable pipeline even in the pandemic situation with shorter lead-in times. In addition, cell-grown vaccines are flexible for altering production scales because stocked cell batches can be easily sub-cultured in large quantity without worrying avian diseases and a resultant decrease in egg production. By World Health Organization, MDCK, PER.C6, and Vero cells are only recommended for manufacturing influenza vaccines. In this review, we discuss the necessity, immunogenicity, and efficacy of cell-grown influenza vaccines compared with egg-based vaccines.

A Novel PA-X Protein Translated from Influenza A Virus Segment 3

The pathogenicity of influenza A viruses is a multigenic trait, which is orchestrated by the global networks between eight viral genomic constituents and their cellular interacting partners. A recent report provided information on the finding of a new PA ribosomal frameshifting product, the PA-X protein, in the influenza A virus segment 3, and an endonuclease property was suggested for a possible role of the PA-X protein. In cultured cells, viral growth was not affected by the PA-X protein expression. However, the reduced pathogenicity of mice appeared to be closely associated with the PA-X protein expression. It was also revealed that the PA-X protein was able to modulate host gene expression. Considered together, the PA-X protein can be a cellular signaling modulator and subsequently control viral pathogenicity. By reviewing recent publications, we present new insights in the contribution of the PA-X protein to the cellular signaling network and the resultant viral pathogenicity.