Human adenovirus infections: update and consideration of mechanisms of viral persistence

Abstract

Purpose of review: To provide an update on recent studies of human adenoviral (HAdV) infections and to explore the mechanisms of viral persistence and the role of persistent infection in disseminated disease in immunocompromised patients.

Recent findings: Human adenoviruses continue to be a problem in ophthalmology clinics and to cause periodic, limited, global outbreaks of respiratory disease. Ad14p1 remains in worldwide circulation and continues to result in miniepidemics of severe respiratory infections. New variants of Ad4 and Ad7 have emerged in both the United States and Asia. The severity of Ad4 infections in outbreaks appears to depend more on preexisting conditions in patients than on genetically determined, viral virulence factors, in contrast to limited evidence of Ad7 mutations that may convey increased viral pathogenesis. Reactivation of persistent adenovirus infection appears to be the primary source of disseminated infections in immunocompromised patients. New studies suggest that establishment of persistent infection and reactivation are related to variations in interferon-mediated control of viral replication.

Summary: Innate immune responses can create a state of adenoviral persistence, and repression of these host defenses can result in reactivation and dissemination of infection. A better definition of the molecular mechanisms of immune-mediated control of viral replication might lead to new strategies for treatment of HAdV reactivation and dissemination.

FIGURE 1.

Model of HAdV persistence and reactivation in the gut. During initial adenovirus infection, sufficient interferon (IFN)-α, β and γ are produced to create a state of viral persistence. Adenovirus (o) is found primarily in lymphoid cells in the gut but is largely absent from highly permissive epithelial cells. Small amounts of virus are produced and shed in the feces. Chemotherapy-induced immunosuppression depletes IFN producing lymphoid cells and represses IFN expression in residual lymphoid cells and other host cells. Repression of the host IFN response allows increased expression of the viral E1A gene, which, in turn, results in increased viral replication in lymphoid cells and lymphoid tissue-associated epithelial cells that can produce large amounts of virus. This viral amplification can result in increased fecal viral shedding, increased tissue invasion and blood borne dissemination of infection.