Ad infections occur worldwide as epidemic, endemic, and sporadic infections. Of the 51 human Ad serotypes currently known, the most common in clinical materials are the respiratory types of subgenus C (Ad1, Ad2, Ad5) and subgenus B (Ad3 and Ad7) (102,103). Along with being an important cause of respiratory tract infections, Ad can also cause conjunctivitis and gastrointestinal disease. Ads have been implicated in aseptic meningitis, encephalitis, hepatitis, and hemorrhagic cystitis and may cause severe disseminated infections in immunocompromised patients of all ages (104). In humans, the majority of Ad infections in immunocompetent hosts are subclinical, meaning that no apparent symptoms are present. This feature has made Ad an attractive platform for numerous gene therapy applications, including cancer. However, like most human virus pathogens, Ads possess a substantial genetic armamentarium to interfere with the immune system of the host to ensure their evolutionary survival (105-108). Infection with Ad results in inhibition of cellular macromolecular synthesis leading to cell damage and death. To avoid clearance from the host, Ads express a number of viral genes that interfere with responses of both the innate and adaptive immune systems. It has been shown that the early Ad genes E1B-55K and E1B-19K inhibit intrinsic p53- and BAX-mediated apoptosis of infected cells (109,110). Expression of virus associated VAI-RNA and E1A genes results in inhibition of cellular responses to interferons (111,112). The Ad E3-19K protein binds major histocompatability complex (MHC) class I molecules in the endoplasmic reticulum, reducing their transport to the cell surface (113,114) and thus preventing the detection and killing of infected cells by cytotoxic T-lymphocytes (CTLs). Lastly, E3-RID, E3-14.7K and E1B-19K proteins interfere with TNF signaling and inhibit cellular apoptosis induced through the death domains (108,115,116).
The data on the immune response to natural Ad infection in humans are scarce. In children with fatal Ad infection, TNFa, IL-6, and IL-8 were detected in the serum (117). However, in patients with only mild disease, none of these cytokines were found at elevated levels in the blood. In a cotton rat model of Ad infection, which closely resemble the pathology of virus infection observed in humans (118,119), two phases in the pathogenesis of Ad2- and Ad5-caused pneumonia have been described. The early histopathologic changes, which are induced by TNF-a and reach the maximum 3 to 5 d after infection, are characterized by mild to moderate injury to bronchial epithelial cells and infiltration of monocytes/macrophages, neutrophils and lymphocytes into peri-broncheal and alveolar regions. During the late phases, 5 to 10 d after infection, a peribroncheal and perivascular infiltration is mostly composed of CD8+ lymphocytes, reflecting a virus-specific cytotoxic T-cell response to infected cells. Ad infection induces the formation of neutralizing antibodies that granted protection against reinfection with the same serotype. In the human population, the prevalence of anti-Ad5 neutralizing antibodies is approx 50 to 80% (120). The high prevalence of pre-existing antibodies is one of the factors that may limit significantly the efficacy of proposed Ad-based gene therapy. A number of approaches are currently under development to avoid neutralization of therapeutic Ad vectors by pre-existing immunity. One of them is conjugation of virus particles to polyethylene glycol (PEG), that was found to protect Ad from antibody binding (121,122). Another approach is the construction of therapeutic vectors using alternative Ad serotypes. Analyses of the prevalence of neutralizing antibodies to different Ad serotypes revealed that neutralizing antibodies to group B Ad11 and Ad35 are least prevalent in human populations (less that 10%) (123). Therefore, significant efforts have been made to construct Ad vectors based on these human serotypes (124,125). Alternatively, vectors based on different animal Ad serotypes (canine Ad, CAV1-3, bovine Ad, BAV-3, chimpanzee Ads) are currently being developed to avoid pre-existing neutralizing immunity (126-130).
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