Compositions and methods for modulating RSV infection and immunity

Abstract

Compositions and methods are provided for the treatment or prevention of RSV disease by modulating RSV infection and immunity. In particular, amino acid sequences in the RSV G glycoprotein, containing the chemokine motif defined as C-X-X-X-C (or CX3C), are identified that are essential in causing RSV infection and disease. The chemokine motif is biologically active and participates in virus binding to and infection of susceptible cells. The prevention or treatment of RSV infection is achieved by interfering with the motif, such as by administering a vaccine in which the motif is altered or by administration or induction of blocking molecules that inhibit the biological activity of the motif.

What is claimed is:  
     
         1 . A composition comprising a blocking molecule that inhibits the biological activity of a CX3C motif of a respiratory syncytial virus G glycoprotein, wherein C is a cysteine residue and X is any amino acid residue other than cysteine.  
     
     
         2 . The composition of  claim 1 , wherein the blocking molecule binds to the respiratory syncytial virus.  
     
     
         3 . The composition of  claim 1  wherein the CX3C motif is at amino acid positions 182-186 of a native respiratory syncytial virus G glycoprotein.  
     
     
         4 . The composition of  claim 1  wherein the blocking molecule is a drug, antibody, peptide, or polypeptide that binds to the CX3C motif of the RSV G glycoprotein.  
     
     
         5 . The composition of  claim 1  wherein the blocking molecule is a drug, antibody, peptide, or polypeptide that binds proximal to the CX3C motif and alters a secondary structure of the motif or sterically blocks respiratory syncytial virus G glycoprotein binding to a CX3C receptor or the biological activity associated with respiratory syncytial virus G glycoprotein binding to a CX3C receptor.  
     
     
         6 . The composition of  claim 1  wherein the blocking molecule is a drug, antibody, peptide, or polypeptide that binds to the CX3C receptor.  
     
     
         7 . The composition of  claim 1 , wherein the blocking agent is a peptide having the sequence TCAAACKRIPNKK (SEQ ID NO: 5).  
     
     
         8 . The composition of  claim 1 , wherein the blocking agent is a peptide having the sequence TCWAACKRIPNKK (SEQ ID NO: 6).  
     
     
         9 . The composition of  claim 1 , wherein the blocking agent is a peptide having the sequence TCNAACKRIPNKK (SEQ ID NO: 7).  
     
     
         10 . The composition of  claim 1 , wherein the blocking agent is a peptide having the sequence TCDAACKRIPNKK (SEQ ID NO: 8).  
     
     
         11 . The composition of  claim 1 , wherein the blocking agent is a peptide having the sequence TCHAACKRIPNKK (SEQ ID NO: 9).  
     
     
         12 . The composition of  claim 1 , wherein the blocking agent is a peptide having the sequence TCMAACKRIPNKK (SEQ ID NO: 10).  
     
     
         13 . The composition of  claim 1 , wherein the blocking agent is a peptide having the sequence TCFAACKRIPNKK (SEQ ID NO: 11).  
     
     
         14 . The composition of  claim 1 , wherein the blocking agent is a peptide having the sequence TCWAICKRIPNK (SEQ ID NO: 3).  
     
     
         15 . The composition of  claim 1 , wherein the blocking agent is a peptide having the sequence NKKPGKKTTKP (SEQ ID NO: 4).  
     
     
         16 . The composition of  claim 1 , wherein the blocking agent is an antibody that binds to the peptide having the sequence TCWAICKRIPNK (SEQ ID NO: 3).  
     
     
         17 . The composition of  claim 1 , wherein the blocking agent is an antibody that binds to the peptide having the sequence NKKPGKKTTKP (SEQ ID NO: 4).  
     
     
         18 . The composition of  claim 1  wherein the biological activity is chemotaxis, cell migration or virus adherence to cells.  
     
     
         19 . A respiratory syncytial virus comprising a CX3C motif of the respiratory syncytial G glycoprotein which is nonfunctional for attachment of the virus to a cell, wherein C is a cysteine residue and X is any amino acid residue other than cysteine.  
     
     
         20 . The respiratory syncytial virus of  claim 19  wherein the virus is a live virus.  
     
     
         21 . The respiratory syncytial virus of  claim 19  wherein the virus is a non-live virus.  
     
     
         22 . A method of inducing an immune response in a subject, comprising administering an immunogenic amount of the composition of  claim 1 .  
     
     
         23 . A method for identifying a substance useful for the treatment or prevention of respiratory syncytial virus disease comprising contacting the substance with a CX3C receptor, in the presence of respiratory syncytial virus G glycoprotein, and detecting inhibition of glycoprotein binding to the CX3C receptor, whereby detection of inhibition of respiratory syncytial virus G glycoprotein binding to the CX3C receptor identifies a substance useful for the treatment or prevetion of respiratory syncytial virus disease.  
     
     
         24 . The method of  claim 23 , wherein the substance binds the CX3C motif of the respiratory syncytial virus G glycoprotein.  
     
     
         25 . The method of  claim 23 , wherein the substance binds the CX3C receptor.  
     
     
         26 . A method for identifying a substance for the treatment or prevention of respiratory synctial virus disease comprising contacting the substance with a CX3C receptor containing cell, in the presence of respiratory syncytial virus, and detecting inihibition of a biological activity associated with respriatory syncytial virus binding to the CX3C receptor, whereby detection of inhibition of a biological activity associated with respriatory syncytial virus binding to the CX3C receptor identifies a substance useful for the treatment or prevention of respiratory syncytial virus disease.  
     
     
         27 . A method for treating respiratory syncytial virus infection in a subject infected with respiratory syncytial virus comprising administering to the subject an effective amount of the composition of  claim 1  in a pharmaceutically acceptable carrier.  
     
     
         28 . A method for treating respiratory syncytial virus infection in a subject infected with respiratory syncytial virus comprising administering to the subject an effective amount of the composition of  claim 16  in a pharmaceutically acceptable carrier.  
     
     
         29 . A method for treating respiratory syncytial virus infection in a subject infected with respiratory syncytial virus comprising administering to the subject an effective amount of the composition of  claim 17  in a pharmaceutically acceptable carrier.  
     
     
         30 . A method for preventing respiratory syncytial virus infection in a subject comprising administering to the subject an immunogenic amount of the virus of  claim 19 .  
     
     
         31 . A method of inducing an immune response in a subject, comprising administering an immunogenic amount of the virus of  claim 19 .  
     
     
         32 . A method of inducing an immune response in a subject, comprising administering an immunogenic amount of the composition of  claim 1  in a pharmaceutically acceptable carrier.  
     
     
         33 . A method of inducing an immune response in a subject, comprising administering an immunogenic amount of the composition of  claim 16  in a pharmaceutically acceptable carrier.  
     
     
         34 . A method of inducing an immune response in a subject, comprising administering an immunogenic amount of the composition of  claim 17  in a pharmaceutically acceptable carrier.