Vitamin A and Vaccination

V itamin A is an essential nutrient that is involved in the regulation of many of the body's functions. Dietary deficiency of this vitamin is associated with several disorders, including blindness, immune defects in the gut, and high susceptibility to measles infection. Sadly, somewhere between 140 and 250 million children under 5 y of age are affected by vitamin A deficiency. Because of its link to immune function, the World Health Organization advocates vitamin A supplementation to enhance measles vaccination in countries where dietary deficiencies are commonplace. However, the extent to which vitamin A deficiency can impact other vaccination strategies is unclear. In the current issue of Viral Immunology, Surman et al. show that vitamin A deficiency significantly disrupts vaccine-induced immunity in the upper and lower respiratory tract. Using Sendai virus infection of mice as a model of respiratory vaccination, the authors investigated antibody-forming cell residence and isotype expression in the context of a vitamin A deficiency. Whereas vaccination of healthy mice elicited an antibody response biased toward IgA in the upper respiratory tract (URT), and IgG in the lower respiratory tract (LRT), vaccination of vitamin A-deficient animals elicited significantly reduced IgA antibodies in the URT in favor of enhanced IgG antibodies in the LRT. These patterns of antibody production were also reflected in the distribution of antibody-forming cells in lymph nodes draining the URT and LRT. These important data further underscore the importance of nutrition in immunity, and suggest that nutritional supplements, which are relatively cheap, may be important for a range of vaccination strategies.

While many pathogenic viruses can be efficiently cleared from the body by an effective immune response, some viruses are able to evade the immune response and persist for the life of the individual. Understanding the mechanisms of viral persistence is essential to developing therapies, or even cures, for this class of viral infections. The current issue of Viral Immunology includes several reports that address this important issue. A prominent example of a virus that is able to establish a persistent infection is the human immunodeficiency virus (HIV). Although cytokines play key roles in modulating disease progression in HIV-infected individuals, there is little known about the relationship between cytokine expression and HIV disease prognosis. Jiao et al. now show that plasma IFN-γ-induced protein 10 (IP-10) was the only cytokine (of 26 cytokines analyzed) that was always positively correlated with CD4 T-cell decline and disease progression. These data suggest the possibility of using IP-10 as a diagnostic marker for rapid disease progression in early HIV-infected individuals. In a second article, the group further shows that CXCR4 co-receptor use during acute HIV infection leads to rapid disease progression. The development of disease during persistent HIV infection is related to the exhaustion and subsequent loss of CD4 T cells, and exhausted CD4 T cells express programmed death receptor 1 (PD-1). Norris et al. show that PD-1 is also expressed on subsets of natural killer (NK) cells and CD8 T cells during chronic HIV-1 infection. Importantly, elevated levels of PD-1 were associated with limited NK cell proliferation, which may have consequences for their maintenance during chronic HIV-1 infection. Another clinically significant virus that establishes a persistent infection is human cytomegalovirus (HCMV). HCMV infection is an important cause of morbidity and mortality in patients with chronic graft-versus-host disease (cGVHD). Namboodiri et al. have investigated the humoral immune responses to HCMV antigens in the context of cGVHD. The authors conclude that anti-HCMV antibodies specific for the UL70 protein might play a protective role in the development of cGVHD. They further note that these findings could lead to a UL70-based adoptive immunotherapy for HCMV disease. Like HCMV, hepatitis C virus (HCV) is also able to establish persistent infection in approximately 80–90% of acutely infected individuals. Persistent HCV infection is a major risk for liver cirrhosis and liver cancer. A review by Amini and Poustchi outlines the findings of several different studies on the host immune response to HCV infection, and the association between cytokine gene polymorphisms and the likelihood of HCV clearance.

Several articles in this issue of Viral Immunology focus on viruses that pose major problems for the agricultural sector. One such example is the influenza virus, which can significantly impair the productivity of swine herds. In this regard, Wei et al. report on the development of a DNA-based vaccine against swine influenza virus infection. The authors' data suggest that plasmids containing repeated epitopes may be a potential vehicle in developing new swine influenza vaccines. Another significant agricultural virus is Marek's disease virus (MDV), which causes weight loss and transient paralysis in domestic chickens. Xu et al. have compared the innate immune responses in strains of chickens that are either resistant or susceptible to the disease, and suggest that there is an underlying immunological mechanism for the neurological dysfunction and the differential responses of the two chicken lines to MDV infection. Virus infections are also a problem for horses. Sponsellar et al. have studied the antibody response to Wyoming wild-type equine infectious anemia virus (EIAV). The authors' data indicate that a single N-glycan located in the virus' principal neutralizing domain regulates the neutralization phenotype of the virus. These data extend our understanding of the mechanisms by which EIAV can escape neutralizing antibody, and are important for future vaccine development. Animal viruses can also be important with respect to human health. The oncolytic properties of Newcastle disease virus (NDV), a chicken pathogen, can be used for human cancer therapy. Oncolytic viruses replicate selectively within tumor cells that have impaired antiviral mechanisms, such as defective IFN responses. Biswas et al. demonstrate a role for retinoic acid-inducible gene I (RIG-I), a cytosolic RNA sensor, in determining NDV sensitivity of human tumor cells. These data may be important for the further development of NDV in oncolytic viral therapies.

Finally, several articles in this issue of Viral Immunology focus on clinically-relevant viruses. Hu et al. have compared the transcriptional profiles of monocytic cells infected with either the severe acute respiratory syndrome (SARS) coronavirus or the 229E coronavirus. Analysis of immune-related gene expression profiles revealed differential regulation of various genes associated with innate immunity. The authors speculate that these differences may be important for the pathogenesis of SARS. The theme of respiratory pathogenesis is continued in a report by Almansa et al., who have studied the association between viral infection and host cytokine responses in 57 chronic obstructive pulmonary disease (COPD) patients hospitalized with an acute exacerbation. Regression analysis indicated that respiratory viral infection (as determined by pharyngeal swabs) correlated with higher levels of IL-6, MCP-1, and admission to the intensive care unit. The authors note that these data indicate a specific role for viral infection in the pathogenesis of COPD exacerbation. Virus infection has also been linked to diabetes. Lindehammer et al. have investigated the relationship between gestational enterovirus (EV) infections and increased risk for type 1 diabetes in the offspring. The data indicate that EV-IgM in early pregnancy increased the risk for islet autoantibodies at delivery in non-diabetic mothers. Lastly, there is an urgent need for new and safe adjuvants for vaccine development. Studies by Chen et al. have investigated whether hemokinin-1 (HK-1), a factor that activates B cells, might be used as a molecular adjuvant for DNA vaccines. The authors show that HK-1 was able to enhance the immunogenicity of hepatitis B surface antigen DNA vaccines, resulting in stronger humoral and memory responses.

Taken together, the articles presented in this issue of Viral Immunology detail considerable advances in the field, ranging from factors that enhance vaccine efficacy (such as vitamin A and vaccine adjuvants), to the role of acute and persistent viral infections in other diseases (such as acquired immune deficiency syndrome and COPD). I thank all of the authors for their contributions.