Cc chemokine receptor 5 dna, new animal models and therapeutic agents for hiv infection

Abstract

The susceptibility of human macrophages to human immunodeficiency virus (HIV) infection depends on cell surface expression of the human CD4 molecule and CC cytokine receptor 5. CCR5 is a member of the 7-transmembrane segment superfamily of G-protein-coupled cell surface molecules. CCR5 plays an essential role in the membrane fusion step of infection by some HIV isolates. The establishment of stable, nonhuman cell lines and transgenic mammals having cells that coexpress human CD4 and CCR5 provides valuable tools for the continuing research of HIV infection. In addition, antibodies which bind to CCR5, CCR5 variants, and CCR5-binding agents, capable of blocking membrane fusion between HIV and target cells represent potential anti-HIV therapeutics for macrophage-tropic strains of HIV.

1 . A method of inhibiting membrane fusion between HIV and a target cell that expresses CCR5 or between an HIV-infected cell and a CD4 positive uninfected cell that expresses CCR5, comprising contacting the target or CD4 positive cell with a fusion-inhibiting effective amount of a CCR5 antibody specific for at least one extracellular loop of CCR5 shown in SEQ ID NO: 5, 6, or 7. 
     
     
         2 . The method of  claim 1 , wherein the antibody is a monoclonal antibody or a polyclonal antibody. 
     
     
         3 . The method of  claim 1 , wherein the contacting is by in vivo administration to a subject. 
     
     
         4 . The method of  claim 3 , wherein the antibody is administered by intravenous, intra-muscular or subcutaneous injections. 
     
     
         5 . The method of  claim 3 , wherein the antibody is administered within a dose range of 0.1 μg/kg to 100 mg/kg. 20 
     
     
         6 . The method of  claim 4 , wherein the antibody is formulated in a pharmaceutically acceptable carrier. 
     
     
         7 . The method of  claim 1 , wherein the antibody is a monoclonal antibody. 25 
     
     
         8 . A method of inhibiting membrane fusion between HIV and a target cell that expresses CCR5 or between an HIV-infected cell and a CD4 positive uninfected cell that expresses CCR5, comprising contacting the target or CD4 positive cell with a fusion-inhibiting effective amount of a CCR5 antibody specific for amino acids 1 to 28 of CCR5 (amino acids 1 to 28 of SEQ ID NO: 4). 
     
     
         9 . The method of  claim 8 , wherein the antibody is a monoclonal antibody or a polyclonal antibody. 
     
     
         10 . The method of  claim 8 , wherein the contacting is by in vivo administration to a subject. 
     
     
         11 . The method of  claim 10 , wherein the antibody is administered by intravenous, intra-muscular or subcutaneous injections. 
     
     
         12 . The method of  claim 10 , wherein the antibody is administered within a dose range of 0.1 μg/kg to 100 mg/kg. 
     
     
         13 . The method of  claim 11 , wherein the antibody is formulated in a pharmaceutically acceptable carrier. 
     
     
         14 . A method of inhibiting membrane fusion between HIV and a target cell that expresses CCR5 or between an HIV-infected cell and a CD4 positive uninfected cell that expresses CCR5, comprising contacting the target or CD4 positive cell with a fusion-inhibiting effective amount of a CCR5 antibody specific for an extracellular loop of CCR5 shown in SEQ ID NO: 5. 
     
     
         15 . The method of  claim 14 , wherein the antibody is a monoclonal antibody or a polyclonal antibody. 
     
     
         16 . The method of  claim 14 , wherein the contacting is by in vivo administration to a subject. 
     
     
         17 . The method of  claim 16 , wherein the antibody is administered by intravenous, intra-muscular or subcutaneous injections. 
     
     
         18 . The method of  claim 16 , wherein the antibody is administered within a dose range of 0.1 μg/kg to 100 mg/kg. 
     
     
         19 . The method of  claim 17 , wherein the antibody is formulated in a pharmaceutically acceptable carrier. 
     
     
         20 . The method of  claim 14 , wherein the antibody is a monoclonal antibody.