Method of inducing neutralizing antibodies to human immunodeficiency virus

Abstract

The present invention relates, in general, to human immunodeficiency virus (HIV), and, in particular, to a method of inducing neutralizing antibodies to HIV and to compounds and compositions suitable for use in such a method.

1 . A method of inducing the production in a patient of anti-human immunodeficiency virus (HIV) antibodies comprising administering to a patient in need thereof an amount of at least one autoantigen cross-reactive with HIV envelope sufficient to effect said induction. 
     
     
         2 . The method according to  claim 1  wherein said autoantigen is cardiolipin, SS-A/RO, double stranded (ds)DNA, centromere B protein or RiBo nucleoprotein (RNP), or fragment thereof that induces production of said antibodies. 
     
     
         3 . The method according to  claim 2  wherein said autoantigen is cardiolipin or fragment thereof that induces production of said antibodies. 
     
     
         4 . The method according to  claim 1  wherein said antibodies bind a gp41 membrane proximal external region (MPER) epitope. 
     
     
         5 . The method according to  claim 4  wherein said MPER epitope comprises the sequence NWFDIT or ELDKWA. 
     
     
         6 . The method according to  claim 1  wherein said method further comprises administering to said patient an HIV envelope protein, polypeptide or peptide comprising an epitope cross-reactive with said autoantigen. 
     
     
         7 . The method according to  claim 6  wherein a DNA sequence encoding said HIV protein, polypeptide or peptide is administered under conditions such that said DNA sequence is expressed and said HIV protein, polypeptide or peptide is thereby produced in said patient. 
     
     
         8 . The method according to  claim 1  further comprising administering to said patient an adjuvant that breaks tolerance to said autoantigen. 
     
     
         9 . The method according to  claim 8  wherein said adjuvant comprises a TRL9 agonist. 
     
     
         10 . The method according to  claim 9  wherein said TRL9 agonist comprises a CpG oligonucleotide. 
     
     
         11 . A composition comprising an autoantigen that is cross-reactive with HIV envelope and an agent that breaks tolerance to said autoantigen. 
     
     
         12 . The composition according to  claim 11  wherein said autoantigen is cardiolipin, SS-A/RO, dsDNA, centromere B protein or RiBo RNP, or fragment thereof comprising an epitope cross-reactive with HIV envelope. 
     
     
         13 . The method according to  claim 11  wherein said agent is a TRL9 agonist. 
     
     
         14 . The method according to  claim 13  wherein said TRL9 agonist comprises a CpG oligonucleotide. 
     
     
         15 . A method of producing autoantibodies that are cross-reactive with HIV envelope comprising isolating B cells from a patient with primary autoimmune disease or from a non-HIV infected patient with an infectious disease selected from the group consisting of syphilis, leishmaniasis and leprosy, and creating therefrom an immortal cell line that produces said autoantibodies. 
     
     
         16 . The method according to  claim 15  wherein said patient is a primary autoimmune patient that is HIV infected or that has received an envelope-based HIV vaccine. 
     
     
         17 . The method according to  claim 15  wherein said B cells are fused with myeloma cells to form hybridomas that produce said autoantibodies. 
     
     
         18 . The method according to  claim 15  wherein said patient is a systemic lupus erythematosus (SLE) patient, an anti-phospholipid antibody syndrome patient or a non-HIV infected patient with an infectious disease selected from the group consisting of syphilis, leishmaniasis and leprosy. 
     
     
         19 . The method according to  claim 18  wherein said patient is a systemic lupus erythematosus (SLE) patient that is HIV infected or that has received an envelope-based HIV vaccine, or said patient is a non-HIV infected patient with an infectious disease selected from the group consisting of syphilis, leishmaniasis and leprosy that has received an envelope-based HIV vaccine. 
     
     
         20 . A method of inducing the production in a patient of anti-HIV antibodies comprising administering to a patient in need thereof an amount of at least one autoantigen cross-reactive with an HIV virion sufficient to effect said induction. 
     
     
         21 . The method according to  claim 20  wherein said autoantigen is a phospholipid or a derivative thereof. 
     
     
         22 . The method according to  claim 21  wherein said phospholipid is cardiolipin, phosphatidylserine, phosphatidylethanolamine, phosphatidylcholine, phosphotidylinositol or sphingomyelin, or derivative thereof. 
     
     
         23 . The method according to  claim 22  wherein said phospholipid is dioleoyl phosphatidylethanolamine (DOPE) (hexagonal phase). 
     
     
         24 . The method according to  claim 20  wherein said autoantigen is cross-reactive with HIV envelope. 
     
     
         25 . The method according to  claim 20  wherein said autoantigen is centromere F protein, or fragment thereof comprising an epitope cross-reactive with the HIV virion. 
     
     
         26 . The method according to  claim 25  wherein said autoantigen is cross-reactive with HIV envelope. 
     
     
         27 . A composition comprising an autoantigen that is cross-reactive with an HIV virion and an agent that breaks tolerance to said autoantigen. 
     
     
         28 . The composition according to  claim 27  wherein said autoantigen is a phospholipid or a derivative thereof. 
     
     
         29 . The composition according to  claim 28  wherein said phospholipid is cardiolipin, phosphatidylserine, phosphatidylethanolamine, phosphatidylcholine, phosphotidylinositol or sphingomyelin, or derivative thereof. 
     
     
         30 . The composition according to  claim 29  wherein said phospholipid is dioleoyl phosphatidylethanolamine (DOPE) (hexagonal phase). 
     
     
         31 . The composition according to  claim 27  wherein said autoantigen is cross-reactive with HIV envelope. 
     
     
         32 . The method according to  claim 1  or  20  wherein said patient is not infected with HIV. 
     
     
         33 . A method of inducing the production in a patient of anti-HIV antibodies comprising administering to a patient in need thereof an amount of at least one liposome-peptide conjugate in an amount sufficient to effect said induction, wherein said peptide comprises a membrane external proximal region (MPER) epitope. 
     
     
         34 . The method according to  claim 33  wherein said peptide comprises the sequence ELDKWAS or WFNITNRW. 
     
     
         35 . The method according to  claim 33  wherein said liposome-peptide conjugate comprises a hydrophobic linker. 
     
     
         36 . An immunogen comprising an MPER epitope embedded in a liposome. 
     
     
         37 . The immunogen according to  claim 36  bound to a detectable label.