Method for preventing HIV-1 infection of CD4+ cells

Abstract

This invention provides methods for inhibiting fusion of HIV-1 to CD4 + cells which comprise contacting CD4 + cells with a non-chemokine agent capable of binding to a chemokine receptor in an amount and under conditions such that fusion of HIV-1 to the CD4 + cells is inhibited. This invention also provides methods for inhibiting HIV-1 infection of CD4 + cells which comprise contacting CD4 + cells with a non-chemokine agent capable of binding to a chemokine receptor in an amount and under conditions such that fusion of HIV-1 to the CD4 + cells is inhibited, thereby inhibiting the HIV-1 infection. This invention provides non-chemokine agents capable of binding to the chemokine receptor and inhibiting fusion of HIV-1 to CD4 + cells. This invention also provides pharmaceutical compositions comprising an amount of the non-chemokine agent capable of binding to the chemokine receptor and inhibiting fusion of HIV-1 to CD4 + cells effective to prevent fusion of HIV-1 to CD4 + cells and a pharmaceutically acceptable carrier.

What is claimed is:  
     
         1 . A method for inhibiting fusion of HIV-1 to CD4 +  cells which comprises contacting CD4 +  cells with a non-chemokine agent capable of binding to a chemokine receptor in an amount and under conditions such that fusion of HIV-1 to the CD4 +  cells is inhibited.  
     
     
         2 . A method for inhibiting HIV-1 infection of CD4 +  cells which comprises contacting CD4 +  cells with a non-chemokine agent capable of binding to a chemokine receptor in an amount and under conditions such that fusion of HIV-1 to the CD4 +  cells is inhibited, thereby inhibiting HIV-1 infection.  
     
     
         3 . The method of  claim 1  or  2 , wherein the non-chemokine agent is an oligopeptide.  
     
     
         4 . The method of  claim 1  or  2 , wherein the non-chemokine agent is a polypeptide.  
     
     
         5 . The method of  claim 1  or  2 , wherein the non-chemokine agent is an antibody or a portion of an antibody.  
     
     
         6 . The method of  claim 1  or  2 , wherein the non-chemokine agent is a nonpeptidyl agent.  
     
     
         7 . A non-chemokine agent capable of binding to a chemokine receptor and inhibiting fusion of HIV-1 to CD4 +  cells.  
     
     
         8 . The non-chemokine agent of  claim 7 , wherein the non-chemokine agent is a oligopeptide.  
     
     
         9 . The non-chemokine agent of  claim 7 , wherein the non-chemokine agent is a nonpeptidyl agent.  
     
     
         10 . The non-chemokine agent of  claim 7 , wherein the non-chemokine agent is a polypeptide.  
     
     
         11 . The non-chemokine agent of  claim 10 , wherein the polypeptide is an antibody or a portion of an antibody.  
     
     
         12 . The non-chemokine agent of  claim 10 , wherein the polypeptide comprises amino acid sequence as set forth in SEQ ID NO:5.  
     
     
         13 . The non-chemokine agent of  claim 10 , wherein the polypeptide comprises the MIP-1β sequence with the deletion of the first seven N-terminal amino acids of said sequence.  
     
     
         14 . The non-chemokine agent of  claim 10 , wherein the polypeptide comprises the MIP-1β sequence with the deletion of the first eight N-terminal amino acids of said sequence.  
     
     
         15 . The non-chemokine agent of  claim 10 , wherein the polypeptide comprises the MIP-1β sequence with the deletion of the first nine N-terminal amino acids of said sequence.  
     
     
         16 . The non-chemokine agent of  claim 10 , wherein the polypeptide comprises the MIP-1β sequence with the deletion of the first ten N-terminal amino acids of said sequence.  
     
     
         17 . The non-chemokine agent of  claim 10 , wherein the polypeptide comprises the MIP-1β sequence with the N-terminal sequence modified by addition of an amino acid or oligopeptide.  
     
     
         18 . The non-chemokine agent of  claim 10 , wherein the polypeptide comprises the MIP-1β sequence with the N-terminal sequence modified by removing the N-terminal alanine and replacing it by serine or threonine and an additional amino acid or oligopeptide or nonpeptidyl moiety.  
     
     
         19 . The non-chemokine agent of  claim 17  or  18 , wherein the additional amino acid is methionine.  
     
     
         20 . An agent capable of binding to CXCR4 and inhibiting HIV-1 infection.  
     
     
         21 . The agent of  claim 20 , wherein the agent is an oligopeptide.  
     
     
         22 . The agent of  claim 20 , wherein the agent is a polypeptide.  
     
     
         23 . The non-chemokine agent of  claim 22 , wherein the polypeptide comprises the SDF-1 sequence with the deletion of the first six N-terminal amino acids of said sequence.  
     
     
         24 . The non-chemokine agent of  claim 22 , wherein the polypeptide comprises the SDF-1 sequence with the deletion of the first seven N-terminal amino acids of said sequence.  
     
     
         25 . The non-chemokine agent of  claim 22 , wherein the polypeptide comprises the SDF-1 sequence with the deletion of the first eight N-terminal amino acids of said sequence.  
     
     
         26 . The non-chemokine agent of  claim 22 , wherein the polypeptide comprises the SDF-1 sequence with the deletion of the first nine N-terminal amino acids of said sequence.  
     
     
         27 . The non-chemokine agent of  claim 22 , wherein the N-terminal glycine of SDF-1 is replaced by serine and derivatized with biotin.  
     
     
         28 . The non-chemokine agent of  claim 22 , wherein the N-terminal glycine of SDF-1 is replaced by serine and derivatized with methionine.  
     
     
         29 . The non-chemokine agent of  claim 22 , wherein the N-terminus of SDF-1 is modified by the addition of a methionine before the terminal glycine.  
     
     
         30 . The agent of  claim 22 , wherein the agent is an antibody or a portion of an antibody.  
     
     
         31 . The agent of  claim 20 , wherein the agent is a non-peptidyl agent.  
     
     
         32 . A pharmaceutical composition comprising an amount of the non-chemokine agent of  claim 7  effective to inhibit fusion of HIV-1 to CD4 +  cells and a pharmaceutically acceptable carrier.  
     
     
         33 . A pharmaceutical composition comprising an amount of the non-chemokine agent of  claim 20  effective to inhibit fusion of HIV-1 to CD4 +  cells and a pharmaceutically acceptable carrier.  
     
     
         34 . A composition of matter capable of binding to a chemokine receptor and inhibiting fusion of HIV-1 to CD4 +  cells comprising a non-chemokine agent linked to a ligand capable of binding to a cell surface receptor of the CD4 +  cells other than the chemokine receptor such that the binding of the non-chemokine agent to the chemokine receptor does not inhibit the binding of the ligand to the other receptor.  
     
     
         35 . The composition of matter of  claim 34 , wherein the cell surface receptor is CD4.  
     
     
         36 . The composition of matter of  claim 34 , wherein the ligand comprises an antibody or a portion of an antibody.  
     
     
         37 . A pharmaceutical composition comprising an amount of the composition of matter of  claim 34  effective to inhibit fusion of HIV-1 to CD4 +  cells and a pharmaceutically acceptable carrier.  
     
     
         38 . A composition of matter capable of binding to the chemokine receptor and inhibiting fusion of HIV-1 to CD4 +  cells comprising a non-chemokine agent linked to a compound capable of increasing the in vivo half-life of the non-chemokine agent.  
     
     
         39 . The composition of matter of  claim 38 , wherein the compound is polyethylene glycol.  
     
     
         40 . A pharmaceutical composition comprising an amount of the composition of  claim 38  effective to inhibit fusion of HIV-1 to CD4 +  cells and a pharmaceutically acceptable carrier.  
     
     
         41 . A method for reducing the likelihood of HIV-1 infection in a subject comprising administering the pharmaceutical composition of  claim 32 ,  33 ,  37  or  40  to the subject.  
     
     
         42 . A method for treating HIV-1 infection in a subject comprising administering the pharmaceutical composition of  claim 32 ,  33 ,  39  or  40  to the subject.  
     
     
         43 . A method for determining whether a non-chemokine agent is capable of inhibiting the fusion of HIV-1 to a CD4 +  cell which comprises: 
 (a) contacting (i) a CD4 +  cell, which is labeled with a first dye, with (ii) a cell expressing the HIV-1 envelope glycoprotein on its surface, which is labeled with a second dye, in the presence of an excess of the agent under conditions permitting the fusion of the CD4 +  cell to the cell expressing the HIV-1 envelope glycoprotein on its surface in the absence of the agent, the first and second dyes being selected so as to allow resonance energy transfer between the dyes;  
 (b) exposing the product of step (a) to conditions which would result in resonance energy transfer if fusion has occurred; and  
 (c) determining whether there is a reduction of resonance energy transfer, when compared with the resonance energy transfer in the absence of the agent, a decrease in transfer indicating that the agent is capable of inhibiting fusion of HIV-1 to CD4 +  cells.  
 
     
     
         44 . The method of  claim 43 , wherein the agent is an oligopeptide.  
     
     
         45 . The method of  claim 43 , wherein the agent is a polypeptide.  
     
     
         46 . The method of  claim 43 , wherein the agent is an antibody or a portion of an antibody.  
     
     
         47 . The method of  claim 43 , wherein the agent is a nonpeptidyl agent.  
     
     
         48 . The method of  claim 43 , wherein the CD4 +  cell is a PM1 cell.  
     
     
         49 . The method of  claim 43 , wherein the cell expressing the HIV-1 envelope glycoprotein is a HeLa cell expressing HIV-1 JR-FL  gp120/gp41.  
     
     
         50 . The method of  claim 43 , wherein the cell expressing the HIV-1 envelope glycoprotein is a HeLa cell expressing HIV-1 LAI  gp120/gp41.