Nipah virus (NiV) is a zoonotic virus causing encephalitis and respiratory disease in humans with a 40-75% mortality rate. NiV is classified as a potential agroterrorism and bioterrorism global pandemic agent. There are currently no approved human vaccines or treatments for NiV infection, hence there is a pressing need to study the mechanism(s) of viral infection and develop antiviral countermeasures. Two functions of the paramyxoviral receptor binding proteins (RBPs, attachment glycoproteins) are well understood: 1) to bind a host cell receptor and 2) to subsequently trigger the fusion glycoprotein F to fuse viral and cellular membranes during host cell entry. Our preliminary data indicate an additional new immunomodulatory function of NiV RBP G: to downregulate the host cellular factor tetherin (BST2), a protein which we also show restricts viral budding.

To better understand how NiV G counteracts tetherin we will explore our overall central hypothesis that paramyxoviruses have evolved a mechanism to counteract tetherin using their RBPs. We will use Nipah virus as a model to study this novel function and its mechanism(s), via the following aims:

Aim 1: Determine the nature of the interaction(s) between NiV G and tetherin. Our preliminary data indicates that tetherin expression is downregulated ~4-fold when cells are transfected with NiV G, and that NiV G and tetherin can co-immunoprecipitate (co-IP). To investigate the nature of these interactions we will: 1A) Determine the putative interactive and functional domain(s) by co-expressing NiV G deletion and point mutants with tetherin and analyzing their levels of interaction and tetherin downregulation; and 1B) Determine the putative interaction sites within cellular compartments.

Aim 2: Determine the role of ephrinBs in NiV G downregulation of tetherin. Prior studies indicate that tetherin can be downregulated via a variety of distinct mechanisms. Our preliminary data suggest that the receptor binding domain of NiV G may be involved. To determine the underlying mechanism of tetherin downregulation by NiV G, we will test the potential role(s) of the NiV G host cell receptors ephrinB2 and ephrinB3.

Aim 3: Identify the potential role(s) of other Henipaviridae or Paramyxoviridae proteins on tetherin downregulation. This aim will test the hypothesis that NiV G downregulation of tetherin is conserved within the Henipaviridae genus, and possibly beyond within the Paramyxoviridae family.