Hendra and nipah infection: pathology, models and potential therapies

Abstract

The Paramyxoviridae family comprises of several genera that contain emerging or re-emerging threats for human and animal health with no real specific effective treatment available. Hendra and Nipah virus are members of a newly identified genus of emerging paramyxoviruses, Henipavirus. Since their discovery in the 1990s, henipaviruses outbreaks have been associated with high economic and public health threat potential. When compared to other paramyxoviruses, henipaviruses appear to have unique characteristics. Henipaviruses are zoonotic paramyxoviruses with a broader tropism than most other paramyxoviruses, and can cause severe acute encephalitis with unique features among viral encephalitides. There are currently no approved effective prophylactic or therapeutic treatments for henipavirus infections. Although ribavirin was empirically used and seemed beneficial during the biggest outbreak caused by one of these viruses, the Nipah virus, its efficacy is disputed in light of its lack of efficacy in several animal models of henipavirus infection. Nevertheless, because of its highly pathogenic nature, much effort has been spent in developing anti-henipavirus therapeutics. In this review we describe the unique features of henipavirus infections and the different strategies and animal models that have been developed so far in order to identify and test potential drugs to prevent or treat henipavirus infections. Some of these components have the potential to be broad-spectrum antivirals as they target effectors of viral pathogenecity common to other viruses. We will focus on small molecules or biologics, rather than vaccine strategies, that have been developed as anti-henipaviral therapeutics.

Fig. 1. Genomic organisation (A) and replication cycle of henipaviruses (B)

(A) The negative genomic RNA is represented in its 3′–5′ orientation. It is composed of 6 units (represented by boxes) encoding in order the nucleoprotein (N), phosphoprotein (P), matrix protein (M), fusion protein (F), attachment protein (G) and RNA polymerase (L). The gene start and stop signals are represented by vertical lines after each unit. The size of each domain is not drawn to scale but the untranslated 3′ regions (5′ ends of the gene units) are unusually long for a Paramyxovirus, but for the L gene. The P gene is the only polycistronic unit and encodes for the V and W proteins after insertion in the mRNA of one or two non-templated G, respectively, in a conserved RNA-editing site. The C protein is translated from an alternate reading frame present in any of the P-mRNA and has its stop codon upstream of the RNA-editing site. (B) The principal described events in the replication cycle of henipaviruses are summarized. After attachment and fusion, the negative genome (vRNA (−)) serves as a template for the transcription of viral mRNAs following a 3′–5′ gradient with significant attenuation at the M-F and G-L junctions, N being transcribed earlier and in greater quantities than L [196]. The vRNA (−) also serves as a template for the replication in cRNA (+), which in turn will be the template for the synthesis of the vRNA (−) that will be incorporated into neovirions. Following traduction of the viral mRNA, different roles of the viral proteins in the inhibition of the interferon signaling pathways (in the cytoplasm and nucleus), regulation of the genome replication, as well as the mechanism of F₀ proteolytic activation via the endosomal Cathepsin-L protein have been identifed. Orchestration of assembly and budding is attributed to the M protein (not represented), though the exact mechanism has not been described yet. The N, P, C, M, F, G and L proteins are incorporated into the virions. With the exception of traduction, assembly and budding, all of the represented steps have been evaluated as targets for the development of anti-henipaviral drugs.