Identification of therapeutic agents for HIV infection

Abstract

A cell surface molecule designated DCIR (for dendritic cells ImmunoReceptor), a member of a recently described family of DC-expressing C-type lectin receptors, has been shown to participate to the capture of human immunodeficiency virus (HIV) and promote infection in trans and in cis of autologous CD4(+) T cells from human immature monocyte-derived DC. The contribution of DCIR to these processes was revealed using DCIR-specific siRNAs and a polyclonal antibody specific for the carbohydrate recognition domain of DCIR. Therapeutic agents for HIV infection are therefore provided herein. These therapeutic agents are useful for impairing the interaction between DCIR and HIV and as such may be useful for treatment or prevention of HIV infection. Also provided are assays for identifying additional therapeutics agents for treatment or prevention HIV infection.

1 . An epitope comprising or consisting of at least 5 amino acids of amino acids 69 to 237 of SEQ ID NO.:6. 
     
     
         2 . The epitope of  claim 1 , wherein said epitope comprises or consist in an amino acid sequence of at least 5 amino acids comprised between amino acids 187-237 of SEQ ID NO.:6. 
     
     
         3 . The epitope of  claim 1 , wherein said epitope comprises or consists in 5 to 15 amino acids of SEQ ID NO.:10, 5 to 16 amino acids of SEQ ID NO.:42 or 5 to 17 amino acids of SEQ ID NO.:43. 
     
     
         4 . A method for treating a subject having an HIV or susceptible of having an HIV infection, the method comprising administering to said mammal a compound capable of impairing an interaction between HIV and DCIR, a compound capable of reducing DCIR expression, or a compound capable of reducing DCIR cell surface expression. 
     
     
         5 . The method of  claim 4 , wherein said compound is an anti-DCIR antibody or an antigen binding fragment thereof. 
     
     
         6 . The method of  claim 5 , wherein said antibody or antigen binding fragment is capable of specific binding to an extracellular region of DCIR. 
     
     
         7 . The method of  claim 5 , wherein said antibody or antigen binding fragment is capable of specific binding to a carboxy terminal region of DCIR. 
     
     
         8 . The method of  claim 5 , wherein said antibody or antigen binding fragment is capable of specific binding to a carbohydrate recognition domain of DCIR. 
     
     
         9 . The method of  claim 5 , wherein said antibody or antigen binding fragment is capable of specific binding to a DCIR epitope comprising at least 5 amino acids of DCIR. 
     
     
         10 . The method of  claim 5 , wherein said antibody or antigen binding fragment is capable of specific binding to a DCIR epitope comprising from 5 to 15 amino acids of SEQ ID NO.:10, from 5 to 16 amino acids of SEQ ID NO.:42 or from 5 to 17 amino acids of SEQ ID NO.:43. 
     
     
         11 . The method of  claim 5 , wherein said antibody or antigen binding fragment is capable of competing with an antibody specific of an epitope comprising at least 5 amino acids of DCIR 
     
     
         12 . The method of  claim 5 , wherein said antibody or antigen binding fragment is capable of competing with an antibody specific of an epitope comprising from 5 to 15 amino acids of SEQ ID NO.:10, with an antibody specific of an epitope comprising from 5 to 16 amino acids of SEQ ID NO.:42 or with an antibody specific of an epitope comprising from 5 to 17 amino acids of SEQ ID NO.:43. 
     
     
         13 . The method of  claim 5 , wherein said antibody is a polyclonal antibody or a monoclonal antibody. 
     
     
         14 . The method of  claim 4 , wherein said compound is capable of hybridizing with a nucleic acid encoding DCIR or with a complement thereof. 
     
     
         15 . The method of  claim 14 , wherein said compound is an antisense nucleic acid capable of hybridizing to a DCIR mRNA expressed from SEQ ID NO.:1. 
     
     
         16 . The method of  claim 14 , wherein said compound is an interfering RNA capable of hybridizing to a nucleic acid sequence having at least 80% identity with a sequence selected from the group consisting of any one of SEQ ID NOs.:2 to 5. 
     
     
         17 . The method of  claim 14 , wherein said compound is an interfering RNA capable  of hybridizing to a sequence selected from the group consisting of any one of SEQ ID NOs.:11 to 41. 
     
     
         18 . A method for identifying a compound that inhibits an interaction between HIV and DCIR, the method comprising contacting a test compound with a preparation comprising DCIR or a cell expressing DCIR and measuring HIV binding to DCIR or to the cell, whereby a diminution of binding in the presence of the test compound is indicative of a compound capable of inhibiting the interaction between HIV and DCIR. 
     
     
         19 . The method of  claim 18 , wherein said test compound is an antibody. 
     
     
         20 . A method for identifying a compound that reduces HIV infection of DCIR expressing cells or HIV dissemination by DCIR expressing cells, the method comprising contacting a test compound with a cell expressing DCIR and measuring HIV replication or transmission, whereby a diminution of HIV replication or transmission in the presence of the test compound is indicative of a compound capable of reducing HIV infection of DCIR expressing cells or HIV dissemination by DCIR expressing cells. 
     
     
         21 . The method of  claim 20 , wherein said test compound is an interfering RNA, an antisense RNA, a ribozyme or a deoxyribozyme.