Pneumovirus ns proteins antagonising the interferon (ifn) response

Abstract

The present invention relates to the use of a pneumovirus NS1 protein and/or NS2 protein or a nucleic acid encoding pneumovirus NS1 protein and/or NS2 protein for the preparation of a pharmaceutical formulation for reducing the immune response mediated by interferon (IFN). The invention further relates to recombinant pneumoviruses, in particular respiratory syncytial viruses (RSV), having an increased, reduced, or lacking a resistance to the interferon (IFN) mediated immune response, recombinant viruses having an increased resistance to the interferon (IFN) mediated immune response, and the use of said viruses in pharmaceutical applications, e.g. as vaccines.

1 . The use of an RSV NS1 and/or NS2 protein or of a nucleic acid sequence encoding NS1 and/or a nucleic acid sequence encoding NS2 for the preparation of a pharmaceutical formulation for reduction of the IFN mediated immune response.  
     
     
         2 . The use according to  claim 1  wherein the immune response is an antiviral response.  
     
     
         3 . The use according to claims  1  or  2  wherein the immune response is inhibited.  
     
     
         4 . The use according to any of the claims  1 - 3  wherein the nucleic acid sequence is DNA or RNA.  
     
     
         5 . The use according to claims  1 - 4  wherein the RSV NS1 and NS2 proteins are used together or wherein the nucleic acid sequence encoding NS1 is used together with the nucleic acid sequence encoding NS2.  
     
     
         6 . The use according to  claim 5  wherein the RSV NS1 protein and NS2 protein are derived from different RSV viruses or wherein the nucleic acid sequence encoding RSV NS1 and the nucleic acid sequence encoding RSV NS2 are derived from different RSV viruses.  
     
     
         7 . The use according to  claim 4  wherein the nucleic acid sequence is contained in a plasmid or in a vector or in a virus derived vector or in a recombinant DNA or RNA virus.  
     
     
         8 . The use according to  claim 7  wherein said vector is a viral gene expression vector used for immunization purposes, in gene therapy or in cytoreductive (cell destruction; anticancer) therapy.  
     
     
         9 . The use according to  claim 7  wherein the virus or the virus derived vector is derived from a DNA virus such as adenovirus (AdV), adeno-associated virus (AAV), herpes virus, or pox virus.  
     
     
         10 . The use according to  claim 7  wherein the virus or the virus derived vector is derived from a positive strand virus, preferably from viruses of the families of Alpha-, Flavi- and Picornaviridae.  
     
     
         11 . The use according to  claim 7  wherein the virus or the virus derived vector is derived from a segmented or non-segmented negative strand RNA virus.  
     
     
         12 . The use according to  claim 7  wherein the RNA virus is derived from the families of Paramyxoviridae, Filoviridae, Bornaviridae, or Rhabdoviridae, particularly for rabies virus.  
     
     
         13 . The use according to  claim 12  wherein the RNA virus is derived from human or animal RSV.  
     
     
         14 . The use according to  claim 13  wherein the nucleic acid sequence encoding NS1 and/or the nucleic acid sequence encoding NS2 are heterologous to said human or animal RSV.  
     
     
         15 . The use according to  claims 1  to  14  wherein the pharmaceutical formulation further contains a vaccine.  
     
     
         16 . The use according to  claims 1  to  15  wherein the RSV NS1 and/or NS2 protein is modified.  
     
     
         17 . The use according to  claim 16  wherein the modification is selected from the group amino acid substitutions, deletions, or insertions.  
     
     
         18 . The use according to claims  16  or  17  wherein the modification results in an increase of the IFN antagonizing activity of the NS1 and/or NS2 protein.  
     
     
         19 . The use according to claims  16  or  17  wherein the modification results in a reduction of the IFN antagonizing activity of the NS1 and/or NS2 protein.  
     
     
         20 . The use of a recombinant RSV having a modified nucleic acid sequence encoding NS1 and/or NS2 for the preparation of a vaccine wherein said modification reduces or abolishes the ability of the virus to escape an IFN mediated immune response of the host.  
     
     
         21 . The use according to  claim 20  wherein the modified nucleic acid sequence encoding NS1 and/or NS2 is homologous or heterologous to said RSV.  
     
     
         22 . The use according to claims  20  or  21  wherein the recombinant RSV is derived from human or bovine RSV.  
     
     
         23 . The use according to claims  20  to 22 wherein the nucleic acid sequence encoding NS1 and/or NS2 is derived from pneumovirus of mice) PVM.  
     
     
         24 . The use according to claims  1  to 23 wherein IFN is type I interferon (IFN alpha or IFN beta).  
     
     
         25 . A method for altering the host range of RSV wherein the nucleic acid sequence encoding NS1 and/or NS2 is replaced by a nucleic acid sequence encoding NS1 and/or NS2 derived from an RSV capable of infecting the desired host.  
     
     
         26 . A recombinant RSV having an altered host range wherein the nucleic acid sequence encoding NS1 and/or NS2 of the virus is replaced by a nucleic acid sequence encoding NS1 and/or NS2 derived from a virus capable of infecting the desired host.  
     
     
         27 . A recombinant virus genetically modified to express the RSV NS1 and/or NS2 protein wherein the expression of the RSV NS1 and/or NS2 protein imparts to said virus or enhances the capability to escape and IFN mediated immune response.  
     
     
         28 . The virus according to  claim 27  wherein said virus is derived from rabies virus.  
     
     
         29 . The virus according to  claims 26  to  28  for use as a vaccine.  
     
     
         30 . The use according to  claim 1  the RSV NS1 and/or NS2 protein or the nucleic acid sequence encoding NS1 and/or the nucleic acid sequence encoding NS2 being derived from BRSV, HRSV, or PVM.  
     
     
         31 . The use according to  claim 30  the RSV NS1 and/or NS2 protein of BRSV, HRSV, or PVM having the sequence according to FIG. 18 or the nucleic acid sequence encoding NS1 and/or the nucleic acid sequence encoding NS2 of BRSV, HRSV, or PVM encoding the sequence according to FIG. 18.