Intestinal HAdV Infection: Tissue Specificity, Persistence, and Implications for Antiviral Therapy

Abstract

Human adenovirus (HAdV) causes infections predominantly in early childhood and the tissue tropism of specific HAdV species determines the clinical manifestation, including infections of the gastrointestinal tract, respiratory tract, and keratoconjunctivitis. Why HAdV shows such a tropism has not yet been fully elucidated, but in the intestine different mechanisms for virus entry or resistence to immune modulatory factors have been described. Recently identified antiviral strategies by interferons provide evidence about the repression of E1A and maybe even promote HAdV persistence. The presence of HAdV in a persistent status in the gut is of importance in the setting of pediatric stem cell transplant recipients where HAdV detection in stool usually preceds clinical signs and severe infections are related to mortality. The reactivation of persistent intestinal HAdV infections in these patients needs further investigation also with regard to successful therapy options. In addition, several newly identified recombinant HAdV types have been isolated from stool samples, thus raising the question of possible recombination events in the gut. In this review, intestinal HAdV infections are discussed in relation to the tissue tropism, persistence, recombination, and new in-vitro models to enhance the knowledge about virus-host interactions and support the development of new treatment approaches.

Keywords: antiviral mechanisms; human adenovirus; intestinal infection; persistence; recombination; tissue tropism.

Figure 1

Different regulation of intestinal HAdV infections by species C and F. The production of HAdV-C types is regulated by human defensin 5 (HD5), whereas HAdV-F types are resistant to HD5, secreted by intestinal Paneth cells. A higher stability of the short fiber protein on HAdV-F types is suggested to also play a role for the frequent gastrointestinal tract infection by these species. Another important regulation might be due to specific cytokines (e.g., IFNα, β, γ, or λ) and their antiviral capacity.