Prophylaxis and therapy of acquired immunodeficiency syndrome

Abstract

An active peptide consisting essentially of 7 to about 30 residence and having a sequence that corresponds to a conserved domain of an HIV protein is disclosed, as is a multimer containing that peptide, an aqueous composition containing the multimer and methods of using and making the same. The aqueous composition containing an immunologically effective amount of an active peptide multimer, when introduced into an immunocompetent host animal in an immunologically effective amount, is capable of inducing cellular immunity against the native HIV protein to which the active peptide of the multimer corresponds in sequence, but is not capable of inducing production of antibodies that immunoreact with that native HIV protein.

What is claimed is:  
     
         1 . A composition containing water having dispersed therein a peptide multimer comprising a plurality of active peptides each of which consists essentially of 7 to about 30 amino acid residues having a sequence that corresponds to a portion of a conserved domain of an HIV protein, said composition, when used to immunize an immunocompetent animal, having the capacity to induce cytotoxic T cell activation to the corresponding native HIV protein but being substantially free from inducing antibodies that immunoreact with said corresponding native HIV protein.  
     
     
         2 . The composition according to  claim 1  wherein the amino acid residue sequence of each of said active peptides corresponds to a portion of a conserved domain of an HIV protein selected from the group consisting of the core, gp41 envelope and gp120 envelope proteins.  
     
     
         3 . The composition according to  claim 2  wherein the sequence of each of said active peptides corresponds to a conserved domain selected from the group consisting of the first, second, third and fifth conserved domains of the gp160 envelope protein.  
     
     
         4 . A composition containing water having dispersed therein a peptide multimer comprising a plurality of active peptides each of which consists essentially of 7 to about 30 amino acid residues having a sequence that corresponds to a conserved domain of an HIV protein selected from the group consisting of the first, second, third and fifth conserved domains of the HIV gp160 envelope protein, said peptide multimer containing said plurality of active peptides bonded together by oxidized cysteine residues at the termini of each of said active peptides or as a micelle formed from the reaction of a C 12 -C 18  fatty acid and the alpha- and epsilon-amino groups of an amino-terminal lysyl residue of a peptide spacer containing one to about five amino acid residues in addition to said lysyl residue added to the amino-terminus of said active peptides, said composition, when used to immunize an immunocompetent animal, having the capacity to induce cytotoxic T cell activation to the corresponding native HIV protein but being substantially free from inducing antibodies that immunoreact with said corresponding native HIV protein.  
     
     
         5 . The composition according to  claim 4  wherein said active peptide consists essentially of a sequence, from left to right and in the direction from amino-terminus to carboxy-terminus, represented by a formula selected from the group consisting of 
 -EQLWVTVYYGVPV-,  
 -VYYGVPVWKEA-,  
 -GVPVWKEATTLFC-,  
 -AHKVWATHACV-,  
 -CVPTNPVPQEVV-,  
 -VLENVTENFNM-,  
 -NNMVEQMHEDII-,  
 -EQMHEDIISLWDQ-,  
 -LWDQSLKPCVKLT-,  
 -SLKPCVKLTPLC-,  
 -SVITQACSKVSFE-,  
 -FEPIPIHYCAFPGF-,  
 -KKFNGTGPCTN-,  
 -GTGPCTNVSTVQC-,  
 -VQCTHGIRPVVSTQ-,  
 -YLRDQQLLGIWGC-,  
 -FLGFLGAAGSTMGAASLTLTVQANQ-,  
 -CRIKQIINMWQGVGKAMYA-,  
 -CRIKQIINMWQGVGKAMYAPPIGGQIRC-,  
 -EGCRQIL-,  
 -ELRSLYNTVAT-,  
 -VIPMFSALSEG-,  
 -AMQMLKET-,  
 -YVDREYKT-,  
 -KTILKALGPA-, and  
 -EMMTACQGV-.  
 
     
     
         6 . The composition according to  claim 4  wherein said active peptide contains a sequence of about 10 to about 25 residues.  
     
     
         7 . The composition according to  claim 6  wherein said active peptide consists essentially of a sequence, from left to right and in the direction from amino-terminus to carboxy-terminus, represented by a formula selected from the group consisting of 
 -LWDQSLKPCVKLT-,  
 -GVPVWKEATTLFC-,  
 -GTGPCTNVSTVQC-,  
 -YLRDQQLLGIWQC-,  
 -FLGFLGAAGSTMGAASLTLTVARQ-,  
 -CRIKQIINMWQGVGKAMYA-,  
 -EQLWVTVYYGVPV-,  
 -VYYGVPVWKEA-, and  
 -SVITQACSKVSFE-.  
 
     
     
         8 . A method of inducing T cell immunity to a preselected native HIV protein in a host animal without inducing substantial production of antibodies that immunoreact with said preselected native HIV protein that comprises introducing into said host animal an immunizing amount of a composition of  claim 1 .  
     
     
         9 . The method according to  claim 8  wherein the amino acid residue sequence of each of said active peptides corresponds to a portion of a conserved domain of an HIV protein selected from the group consisting of the core, gp41 envelope and gp120 envelope proteins.  
     
     
         10 . A method of inducing T cell immunity to a preselected native HIV protein in a host animal without inducing substantial production of antibodies that immunoreact with said preselected native HIV protein that comprises introducing into said host animal an immunizing amount of a composition of  claim 4 .  
     
     
         11 . The method according to  claim 10  wherein said active peptide consists essentially of a sequence, from left to right and in the direction from amino-terminus to carboxy-terminus, represented by a formula selected from the group consisting of 
 -EQLWVTVYYGVPV-,  
 -VYYGVPVWKEA-,  
 -GVPVWKEATTLFC-,  
 -AHKVWATHACV-,  
 -CVPTNPVPQEVV-,  
 -VLENVTENFNM-,  
 -NNMVEQMHEDII-,  
 -EQMHEDIISLWDQ-,  
 -LWDQSLKPCVKLT-,  
 -SLKPCVKLTPLC-,  
 -SVITQACSKVSFE-,  
 -FEPIPIHYCAFPGF-,  
 -KKFNGTGPCTN-,  
 -GTGPCTNVSTVQC-,  
 -VQCTHGIRPVVSTQ-,  
 -YLRDQQLLGIWGC-,  
 -FLGFLGAAGSTMGAASLTLTVQANQ-,  
 -CRIKQIINMWQGVGKAMYA-,  
 -CRIKQIINMWQGVGKAMYAPPIGGQIRC-,  
 -EGCRQIL-,  
 -ELRSLYNTVAT-,  
 -VIPMFSALSEG-,  
 -AMQMLKET-,  
 -YVDREYKT-,  
 -KTILKALGPA-, and  
 -EMMTACQGV-.  
 
     
     
         12 . The method according to  claim 10  wherein said active peptides consists essentially of a sequence, from left to right and in the direction from amino-terminus to carboxy-terminus, represented by a formula selected from the group consisting of 
 -LWDQSLKPCVKLT-,  
 -GVPVWKEATTLFC-,  
 -GTGPCTNVSTVQC-,  
 -YLRDQQLLGIWQC-,  
 -FLGFLGAAGSTMGAASLTLTVARQ-,  
 -CRIKQIINMWQGVGKAMYA-,  
 -EQLWVTVYYGVPV-,  
 -VYYGVPVWKEA-, and  
 -SVITQACSKVSFE-.  
 
     
     
         13 . A peptide containing up to about 30 amino acid residues that includes a peptide having a sequence that consists essentially of an amino acid residue sequence, from left to right and in the direction from amino-terminus to carboxy-terminus represented by a formula selected from the group consisting of 
 -YLRDQQLLGIWGC-,    -FLGFLGAAGSTMGAASLTLTVARQ-,    -EQLWVTVYYGVPV-,    -VYYGVPVWKEA-,    -SVITQACSKVSFE-,    -GVPVWKEATTLFC-,    -AHKVWATHACV-,    -CVPTNPVPQEVV-,    -SLKPCVKLTPLC-,    -FEPIPIHYCAFPGF-,    -EGCRQIL-,    -ELRSLYNTVAT-,    -VIPMFSALSEG-,    -AMQMLKET-,    -YVDREYKT-,    -KTILKALGPA-, and    -EMMTACQGV-.    
     
     
         14 . The peptide according to  claim 13  wherein said amino acid residue sequence, from left to right and in the direction from amino-terminus to carboxy-terminus, is represented by a formula selected from the group consisting of 
 -YLRDQQLLGIWGC-,  
 -FLGFLGAAGSTMGAASLTLTVARQ-,  
 -EQLWVTVYYGVPV-,  
 -VYYGVPVWKEA-,  
 -SVITQACSKVSFE-, and  
 -GVPVWKEATTLFC-.  
 
     
     
         15 . The peptide according to  claim 13  wherein said amino acid residue sequence, from left to right and in the direction from amino-terminus to carboxy-terminus, is represented by a formula selected from the group consisting of 
 YLRDQQLLGIWGC,  
 FLGFLGAAGSTMGAASLTLTVARQ,  
 EQLWVTVYYGVPV,  
 VYYGVPVWKEA,  
 SVITQACSKVSFE,  
 GVPVWKEATTLFC,  
 AHKVWATHACV,  
 CVPTNPVPQEVV,  
 SLKPCVKLTPLC,  
 FEPIPIHYCAFPGF,  
 EGCRQIL,  
 ELRSLYNTVAT,  
 VIPMFSALSEG,  
 AMQMLKET,  
 YVDREYKT,  
 KTILKALGPA, and  
 EMMTACQGV.  
 
     
     
         16 . The peptide according to  claim 13  wherein said amino acid residue sequence, from left to right and in the direction from amino-terminus to carboxy-terminus, is represented by a formula selected from the group consisting of 
 YLRDQQLLGIWGC,  
 FLGFLGAAGSTMGAASLTLTVARQ,  
 EQLWVTVYYGVPV,  
 VYYGVPVWKEA,  
 SVITQACSKVSFE, and  
 GVPVWKEATTLFC.  
 
     
     
         17 . A method of killing target cells that exhibit an HIV protein or a portion of an HIV protein on their cell surfaces that comprises the steps of 
 (a) contacting target cells that exhibit an HIV protein or a portion of an HIV protein on their cell surfaces with a killing effective amount of cytotoxic T cells that have been immunized with a composition of  claim 1;  and    (b) maintaining said contact for a time period sufficient for said cytotoxic T cells to kill said target cells.    
     
     
         18 . A method of killing target cells that exhibit an HIV protein or a portion of an HIV protein on their cell surfaces that comprises the steps of 
 (a) contacting target cells that exhibit an HIV protein or a portion of an HIV protein on their cell surfaces with a killing effective amount of cytotoxic T cells that have been immunized with a composition of claim  4 ; and    (b) maintaining said contact for a time period sufficient for said cytotoxic T cells to kill said target cells.    
     
     
         19 . A peptide multimer comprising a plurality of active peptides bonded together by oxidized cysteine residues at the termini of each of said active peptides, each of said active peptides consisting essentially of 7 to about 30 amino acid residues having a sequence that corresponds to a conserved domain of an HIV protein, said peptide multimer, when dispersed in an aqueous composition and introduced in an immunologically effective amount into an immunocompetent host animal, having the capacity to induce cytotoxic T cell activation to the corresponding native HIV protein, but being substantially free from inducing antibodies that immunoreact with said corresponding native HIV protein.  
     
     
         20 . The peptide multimer according to  claim 19  wherein the amino acid residue sequence of each of said active peptides corresponds to a portion of a conserved domain of an HIV protein selected from the group consisting of the core, gp41 envelope and gp120 envelope proteins.  
     
     
         21 . The peptide multimer according to  claim 20  wherein said active peptide consists essentially of a sequence, from left to right and in the direction from amino-terminus to carboxy-terminus, represented by a formula selected from the group consisting of 
 -EQLWVTVYYGVPV-,  
 -VYYGVPVWKEA-,  
 -GVPVWKEATTLFC-,  
 -AHKVWATHACV-,  
 -CVPTNPVPQEVV-,  
 -VLENVTENFNM-,  
 -NNMVEQMHEDII-,  
 -EQMHEDIISLWDQ-,  
 -LWDQSLKPCVKLT-,  
 -SLKPCVKLTPLC-,  
 -SVITQACSKVSFE-,  
 -FEPIPIHYCAFPGF-,  
 -KKFNGTGPCTN-,  
 -GTGPCTNVSTVQC-,  
 -VQCTHGIRPVVSTQ-,  
 -YLRDQQLLGIWGC-,  
 -FLGFLGAAGSTMGAASLTLTVQANQ-,  
 -CRIKQIINMWQGVGKAMYA-,  
 -CRIKQIINMWQGVGKAMYAPPIGGQIRC-,  
 -EGCRQIL-,  
 -ELRSLYNTVAT-,  
 -VIPMFSALSEG-,  
 -AMQMLKET-,  
 -YVDREYKT-,  
 -KTILKALGPA-, and  
 -EMMTACQGV-.  
 
     
     
         22 . The peptide multimer according to  claim 20  wherein said active peptide consists essentially of a sequence, from left to right and in the direction from amino-terminus to carboxy-terminus, represented by a formula selected from the group consisting of 
 -LWDQSLKPCVKLT-,  
 -GVPVWKEATTLFC-,  
 -GTGPCTNVSTVQC-,  
 -YLRDQQLLGIWQC-,  
 -FLGFLGAAGSTMGAASLTLTVARQ-,  
 -CRIKQIINMWQGVGKAMYA-,  
 -EQLWVTVYYGVPV-,  
 -VYYGVPVWKEA-, and  
 -SVITQACSKVSFE-.  
 
     
     
         23 . A di-amide-peptide reaction product formed from a C 12 -C 18  fatty acid and the alpha- and epsilon-amino groups of the amino-terminal lysyl residue of a composite polypeptide, said composite polypeptide consisting essentially of an amino-terminal lysyl residue spacer peptide containing one to about five amino acid residues in addition to said lysyl residue peptide bonded to the amino-terminus of a peptide containing 7 to about 30 amino acid residues having a sequence that corresponds to a portion of a conserved domain of an HIV protein, said di-amide peptide reaction product, when dispersed in an aqueous composition as a peptide multimer micelle and used to immunize an immunocompetent animal, having the capacity to induce ctyotoxic T cell activation to the corresponding native HIV protein, but being substantially free from inducing antibodies that immunoreact with said corresponding native HIV protein.  
     
     
         24 . The di-amide reaction product according to  claim 24  wherein said C 12 -C 18  fatty acid is palmitic acid and said spacer peptide has the sequence, from amino-terminus to carboxy-terminus and from left to right, represented by the formula Lys-Gly-Gly.  
     
     
         25 . The di-amide reaction product according to  claim 23  wherein said active peptide consists essentially of a sequence, from left to right and in the direction from amino-terminus to carboxy-terminus, represented by a formula selected from the group consisting of 
 -EQLWVTVYYGVPV-,  
 -VYYGVPVWKEA-,  
 -GVPVWKEATTLFC-,  
 -AHKVWATHACV-,  
 -CVPTNPVPQEVV-,  
 -VLENVTENFNM-,  
 -NNMVEQMHEDII-,  
 -EQMHEDIISLWDQ-,  
 -LWDQSLKPCVKLT-,  
 -SLKPCVKLTPLC-,  
 -SVITQACSKVSFE-,  
 -FEPIPIHYCAFPGF-,  
 -KKFNGTGPCTN-,  
 -GTGPCTNVSTVQC-,  
 -VQCTHGIRPVVSTQ-,  
 -YLRDQQLLGIWGC-,  
 -FLGFLGAAGSTMGAASLTLTVQANQ-,  
 -CRIKQIINMWQGVGKAMYA-,  
 -CRIKQIINNWQGVGKAMYAPPIGGQIRC-,  
 -EGCRQIL-,  
 -ELRSLYNTVAT-,  
 -VIPMFSALSEG-,  
 -AMQMLKET-,  
 -YVDREYKT-,  
 -KTILKALGPA-, and  
 -EMMTACQGV-.  
 
     
     
         26 . The di-amide reaction product according to  claim 23  wherein said active peptide consists essentially of a sequence, from left to right and in the direction from amino-terminus to carboxy-terminus, represented by a formula selected from the group consisting of 
 -LWDQSLKPCVKLT-,  
 -GVPVWKEATTLFC-,  
 -GTGPCTNVSTVQC-,  
 -YLRDQQLLGIWQC-,  
 -FLGFLGAAGSTMGAASLTLTVARQ-,  
 -CRIKQIINMWQGVGKAMYA-,  
 -EQLWVTVYYGVPV-,  
 -VYYGVPVWKEA-, and  
 -SVITQACSKVSFE-.