Chimeric hiv fusion proteins as vaccines

Abstract

A chimeric fusion protein useful as an immunogen for inducing HIV antigen-specific immune responses contains a first polypeptidyl region and a second polypeptidyl region. The first polypeptidyl region includes a Pseudomonas Exotoxin A (PE) binding domain and a PE translocation domain. The second polypeptidyl region includes (i) a first peptidyl segment containing a fragment of gp120 C1 domain, located at the N-terminus of the second peptidyl region; (ii) a second peptidyl segment containing a fragment of gp120 C5 domain, located at the C-terminus of the first peptidyl segment; and (iii) a third peptidyl segment containing a fragment of gp41, located at the C-terminus of the second peptidyl segment. The second polypeptidyl region contains an antigenic determinant specific to one subtype of HIV. An intermediate polypeptide containing a non-Env, HIV antigenic determinant selected from Gag24, Nef, Tat and Rev may be included.

1 . A chimeric fusion protein useful as an immunogen for inducing HIV antigen-specific immune responses comprising:
 a. a first polypeptidyl region containing a Pseudomonas Exotoxin A (PE) binding domain and a PE translocation domain, located at the N-terminus of the fusion protein; and   b. a second polypeptidyl region located at the C-terminus of the fusion protein, including:
 i. a first peptidyl segment containing a fragment of gp120 C1 domain, located at the N-terminus of the second peptidyl region; 
 ii. a second peptidyl segment containing a fragment of gp120 C5 domain, located at the C-terminus of the first peptidyl segment; and 
 iii. a third peptidyl segment containing a fragment of gp41 amino acid sequence, located at the C-terminus of the second peptidyl segment, 
   
       wherein the second polypeptidyl region contains an antigenic determinant which is specific to one subtype of HIV. 
     
     
         2 . The fusion protein of  claim 1  further comprising an endoplasmic reticulum retention sequence at the C-terminus of the fusion protein. 
     
     
         3 . The fusion protein of  claim 1 , wherein the one subtype of HIV is at least one selected from the group consisting of HIV subtypes A, B, C, D, E, F, G, H, J and K. 
     
     
         4 . The fusion protein of  claim 1  further comprising an intermediate polypeptidyl region between the first and the second polypeptidyl regions, wherein the intermediate polypeptidyl region contains a non-Env, HIV antigenic determinant. 
     
     
         5 . The fusion protein of  claim 4 , wherein the intermediate polypeptidyl region comprises an HIV protein, or a fragment thereof, which is at least one selected from the group consisting of Gag24, Nef, Tat and Rev. 
     
     
         6 . The fusion protein of  claim 4 , wherein the intermediate polypeptidyl region comprises Gag24 amino acid sequence or a fragment thereof. 
     
     
         7 . The fusion protein of  claim 6 , wherein the intermediate polypeptidyl region comprises an N- or C-terminus of Gag24 amino acid sequence. 
     
     
         8 . The fusion protein of  claim 4 , wherein the intermediate polypeptidyl region comprises the amino acid sequence set forth by SEQ ID NO: 151. 
     
     
         9 . A fusion protein useful as an immunogen for inducing HIV antigen-specific immune responses comprising:
 a. a first polypeptidyl region containing a PE binding domain and a PE translocation domain, located at the N-terminus of the fusion protein; and   b. a second polypeptidyl region containing an HIV protein or a fragment thereof, located at the C-terminus of the fusion protein,   
       wherein the second polypeptidyl region contains an antigenic determinant which is specific to one subtype of HIV. 
     
     
         10 . The fusion protein of  claim 9  further comprising an endoplasmic reticulum retention sequence at the C-terminus of the fusion protein. 
     
     
         11 . The fusion protein of  claim 9 , wherein the second polypeptidyl region contains a fragment of HIV Env. 
     
     
         12 . The fusion protein of  claim 9 , wherein the second polypeptidyl region contains one or more than one fragment of gp120 V3 domain. 
     
     
         13 . The fusion protein of  claim 12 , wherein the second polypeptidyl region contains the amino acid sequence set forth by SEQ ID NO: 6. 
     
     
         14 . The fusion protein of  claim 9 , wherein the second polypeptidyl region comprises an HIV protein, or a fragment thereof, which is at least one selected from the group consisting of Gag24, Nef, Tat and Rev. 
     
     
         15 . The fusion protein of  claim 14 , wherein the second polypeptidyl region comprises HIV Gag24 amino acid sequence or a fragment thereof. 
     
     
         16 . The fusion protein of  claim 9 , wherein the second polypeptidyl region is a chimeric protein comprising:
 i. a first peptidyl segment containing a fragment of gp120 C1 domain, located at the N-terminus of the second peptidyl region;   ii. a second peptidyl segment containing a fragment of gp120 C5 domain, located at the C-terminus of the first peptidyl segment; and   iii. a third peptidyl segment containing a fragment of gp41 amino acid sequence, located at the C-terminus of the second peptidyl segment.   
     
     
         17 . The fusion protein of  claim 16  further comprising an endoplasmic reticulum retention sequence at the C-terminus of the fusion protein. 
     
     
         18 . The fusion protein of  claim 16 , wherein the second polypeptidyl region comprises the amino acid sequence set forth by SEQ ID NO: 7. 
     
     
         19 . The fusion protein of  claim 9  further comprising an intermediate polypeptidyl region between the first and the second polypeptidyl regions, wherein the intermediate polypeptidyl region contains a non-Env, HIV antigenic determinant. 
     
     
         20 . The fusion protein of  claim 9 , wherein the intermediate polypeptidyl region comprises an HIV protein, or a fragment thereof, which is at least one selected from the group consisting of Gag24, Nef, Tat and Rev.