Henipavirus outbreaks to antivirals: the current status of potential therapeutics

Abstract

The henipaviruses, Hendra virus and Nipah virus, are classic examples of recently emerged viral zoonoses. In a relatively short time since their discoveries in the mid and late 1990s, respectively, a great deal of new information has been accumulated detailing their biology and certain unique characteristics. Their broad species tropism and abilities to cause severe and often fatal respiratory and/or neurologic disease in both animals and humans has sparked considerable interest in developing effective antiviral strategies to prevent or treat henipavirus infection and disease. Here, recent findings on the few most advanced henipavirus countermeasures are summarized and discussed.

Figure 1

Absence of HeV antigen in the lung of m102.4 treated African green monkeys. Localization of HeV antigen by immunohistochemical stain in the middle lung, (a) monkey in the m102.4 treatment group beginning at 72 hr, and (b) a control animal (viral antigen is red staining). Sections were stained with a NiV nucleoprotein (N) specific rabbit polyclonal antibody and images were obtained at an original magnification of at 20X. These images were originally published in Bossart et al, [69] and reformatted with permission.

Figure 2

Hendra virus soluble G glycoprotein subunit vaccine and details of the ephrin binding site on the G glycoprotein globular head in comparison to the m102.4 binding site. The HeV-sG glycoprotein subunit vaccine consists of the entire predicted ectodomain (amino acids 76–604). (a) HeV-sG shown as the dimer with one monomer colored red and the other is blue. The secondary structure elements of the two globular head domains are derived from the crystal structure of the HeV G head domain, which also revealed that all five predicted N-linked glycosylation sites (N306, N378, N417, N481 and N529) were occupied by carbohydrate moieties (gray spheres) [35]. N378 is not modeled in the figure due to weak electron density. The G glycoprotein head domain folds as a six-blade β-propeller. The structure of the entire HeV G stalk domain (residues 71–173) has not been determined, but here the stalk regions (residues 77–136) of each monomer are modeled [78] and are not a continuous helix. The HeV-sG stalk residues 98–135 appear equivalent to the HN glycoprotein stalk helix domain of the recently reported NDV structure [79]. Here, the position of HeV sG head dimer and stalks are oriented based on the alignment to the NDV structure. The ephrin receptor binding face of the red monomer is facing out and that of the blue monomer is facing left.