The Quality of Papers in Viral Immunology Continues to Rise

T he quality of papers received by Viral Immunology continues to rise and this issue is no exception. A highlight of the current issue is a paper by Sant and colleagues in which the authors analyze the specificity of CD4 T cells during the primary immune response to influenza A virus. The authors point out that our understanding of CD4 T-cell diversity and specificity is limited, especially with respect to the relationship between viral proteins targeted by T cells and the major histocompatibility complex (MHC)-restricting elements involved. The authors address this issue using an influenza virus model and show that the distribution of CD4 T-cell specificities for different viral proteins varied significantly with the MHC class II molecule expressed. In SJL mice, the majority of T-cell epitopes were derived from the hemagglutinin (HA) protein, whereas in C57BL/10 mice, the majority of T-cell epitopes were derived from the nucleoprotein. Clearly, these findings have important implications for vaccine design given the outbred nature of the human population.

A key function of CD4 T cells in a vaccine context is the provision of help for the production of antiviral, and hopefully virus-neutralizing antibodies. Therefore, a solid understanding of the antibody targets in the pathogen is essential to the development of optimal vaccines. With this in mind, Rudneva and associates have analyzed the antigenic epitopes recognized by monoclonal antibodies against avian H5N1 influenza virus isolated in western Siberia. The data reveal several amino acid residues in the globular head of the HA that appear to be important for antibody recognition. The immunogenicity of the HA protein of an H5N1 strain of influenza has also been analyzed by Hogan and colleagues. The data show that recombinant H5 HA protein-based vaccines can rapidly induce high serum antibody titers and may be more effective than either inactivated influenza virus or DNA vaccines in a cat model. Two papers address similar issues of antigenicity in coronaviruses. Liu and colleagues describe a linear B-cell epitope at the N-terminus of the avian infectious bronchitis virus nucleocapsid protein. This epitope is conserved among avian coronaviruses, suggesting that it might be useful for clinical applications. Du and associates have focused on the spike protein of the coronavirus responsible for severe acute respiratory syndrome. Since the spike protein is important for infection it is therefore a strong target for vaccine development. The data show that a 219-mer protein from the receptor-binding domain could induce strong humoral and cellular immune responses and high titer of neutralizing antibodies in the vaccinated mice.

In addition to helping B cells produce antibodies, T cells express a variety of effector and regulatory functions. In the case of human immunodeficiency virus (HIV), these T-cell functions can become attenuated with prolonged viral infection. This loss of function can be associated with a subsequent loss of immune control of the virus. Bernard and colleagues have assessed the kinetics with which HIV-specific T cells lose function. The authors show that functional defects start to accumulate in T cells 6 mo after infection. Defects include reduced poly-functionality and proliferative capacity, both of which are likely to have negative consequences for the control of persistent viral replication.

The capacity of a vaccine to elicit an immune response depends on the presence of an adjuvant. Adjuvants are immunostimulatory compounds that elicit innate inflammatory responses necessary for the optimal priming and expression of adaptive immunity. Bacterial flagellin has been shown to exhibit potent adjuvant properties and Mizel and colleagues have evaluated its capacity to boost humoral responses to vaccinia antigens in mice. Virus neutralization titers correlated with protection, but interestingly, depletion of complement resulted in a marked loss of protection against vaccinia virus challenge in vaccinated mice. The data suggest that vaccinia proteins are effective in eliciting protective immunity against vaccinia virus that is dependent, in large part, on complement. Several other papers also address the role of innate and adaptive immunity in the control of viral infections. Rowland and colleagues have investigated the intensity and timing of the early cytokine responses to porcine reproductive and respiratory syndrome virus (PRRSV) infection to determine their utility as a predictor of persistence. The authors show that variation in multiple serum cytokines was significantly correlated with virus level and argue that cytokine activities should be considered when understanding the role of immunity in persistence. In another study, Sharif and colleagues have analyzed the innate and adaptive immune response to Marek's disease virus (MDV) of chickens. The authors demonstrate that although the expression of components of the IFN-γ receptor complex was significantly downregulated 4 d post-infection, a number of other IFN-γ-signaling molecules, including signal transducer and activator of transcription 1, interferon responsive factor 1, and class II transactivator were significantly upregulated. These changes illuminate the possible mechanisms by which MDV may evade host immunity.

One of the challenges of studying immune responses to infection is to identify relevant animal models or cell systems. For example, studies on epithelial immune responses to rotavirus infection have been conducted in transformed cell lines. Liu and colleagues have developed a non-transformed porcine jejunum epithelial cell line (IPEC-J2) as an in-vitro model of rotavirus infection. Using this model they were able to directly test the impact of probiotic bacteria on innate immune responses to infection. Interestingly, Lactobacillus rhamnosus downregulated mucus secretion and the IL-6 response and elicited a protective effect that was associated with increased TLR2 expression on intestinal epithelial cells. The studies demonstrate the value of this model system for studying rotavirus infections.

Finally, Talaat and colleagues have investigated the role of angiogenesis in hepatitis C virus (HCV)-related cirrhosis and the development of hepatocellular carcinoma. The authors note a significant correlation between serum levels of vascular endothelial growth factor, platelet-derived growth factor, tumor necrosis factor-α and the grade of the disease. These parameters may be helpful to detect the progression of the disease and suggest a beneficial role for anti-angiogenic therapy.