Coagulation Factor IX Mediates Serotype-Specific Binding of Species A Adenoviruses to Host Cells

Abstract

Human species A adenoviruses (HAdVs) comprise three serotypes: HAdV-12, -18, and -31. These viruses are common pathogens and cause systemic infections that usually involve the airways and/or intestine. In immunocompromised individuals, species A adenoviruses in general, and HAdV-31 in particular, cause life-threatening infections. By combining binding and infection experiments, we demonstrate that coagulation factor IX (FIX) efficiently enhances binding and infection by HAdV-18 and HAdV-31, but not by HAdV-12, in epithelial cells originating from the airways or intestine. This is markedly different from the mechanism for HAdV-5 and other human adenoviruses, which utilize coagulation factor X (FX) for infection of host cells. Surface plasmon resonance experiments revealed that the affinity of the HAdV-31 hexon-FIX interaction is higher than that of the HAdV-5 hexon-FX interaction and that the half-lives of these interactions are profoundly different. Moreover, both HAdV-31-FIX and HAdV-5-FX complexes bind to heparan sulfate-containing glycosaminoglycans (GAGs) on target cells, but binding studies utilizing cells expressing specific GAGs and GAG-cleaving enzymes revealed differences in GAG dependence and specificity between these two complexes. These findings add to our understanding of the intricate infection pathways used by human adenoviruses, and they may contribute to better design of HAdV-based vectors for gene and cancer therapy. Furthermore, the interaction between the HAdV-31 hexon and FIX may also serve as a target for antiviral treatment.In immunocompetent individuals, human adenoviruses (HAdVs) cause self-limiting diseases that affect the intestine, airways, urinary tract, tonsils, and/or eyes (74). Species A HAdVs (HAdV-12, -18, and -31) are common pathogens in humans (64) and are associated with cryptic, disseminated gastrointestinal and/or respiratory infections, usually in children under the age of 4 years (2,14,48,60). In immunocompromised individuals (AIDS patients, organ transplant patients, or patients with congenital immune deficiencies), species A HAdVs in general, and HAdV-31 in particular, cause severe and sometimes lethal infections (18,25,29,35,(37)(38). In this group of patients, the symptoms are similar to those in immunocompetent patients but more severe, and they also include hepatitis.The icosahedral adenovirus particle is composed of three major capsomers: the fiber, the penton base, and the hexon protein. The trimeric fiber proteins contain the terminal knob domain, which directly binds virions to cellular receptors, such as the coxsackievirus and adenovirus receptor (CAR) (11, 58, 63), desmoglein 2 (68), CD46 (22, 42, 61), or sialic-acid-containing glycans (7-8, 47), in a species-and/or serotype-specific manner. The pentameric penton base proteins contain conserved RGD motifs (except in HAdV-40 and HAdV-41) (5) that interact with cellular integrins (44) in vitro, resulting in endocytosis (10, 72) and endosomal release (69, 71). The trimeric hexon protein is the major building bloc...

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