Compositions and methods for inhibiting human immunodeficiency virus infection by down-regulating human cellular genes

Abstract

The present invention relates to the identification of several human genes as cellular targets for the design of therapeutic agents for suppressing human immunodeficiency virus (HIV) infection. These genes encode intracellular products which appear to be necessary for HIV replication, as evidenced by an inhibition of HIV infection in cells in which the expression of these genes is down-regulated. Therefore, inhibitors of these genes and their encoded products may be used as therapeutic agents for the treatment and/or prevention of HIV infection. In addition, the invention also relates to methods for identifying additional cellular genes as therapeutic targets for suppressing HIV infection, and methods of using such cellular genes and their encoded products in screening assays for selecting additional inhibitors of HIV.

What is claimed is:  
     
         1 . An HIV inhibitory composition, comprising an isolated polynucleotide corresponding to a portion of a cellular gene or a complement thereof, said gene encodes and intracellular product which is necessary for a productive HIV infection, said polynucleotide is operably linked to a regulatory sequence, and expression of said polynucleotide in a host cell inhibits infection by HIV.  
     
     
         2 . The composition of  claim 1 , in which inhibition of infection by HIV is measured by continued CD4 expression in the cells following HIV infection.  
     
     
         3 . The composition of  claim 1 , in which inhibition of infection by HIV is measured by decreased viral p24 expression in the cells following HIV infection.  
     
     
         4 . A method for protecting host cells from HIV infection, comprising introducing an effective amount of the composition of  claim 1 .  
     
     
         5 . The method of  claim 4 , in which the composition is introduced into the host cells in vitro.  
     
     
         6 . The method of  claim 4 , in which the composition is introduced into the host cells in vivo.  
     
     
         7 . A method for treating HIV infection, comprising administering a therapeutically effective amount of the composition of  claim 1  to an individual to inhibit HIV infection.  
     
     
         8 . A method for inhibiting HIV infection, comprising administering a therapeutically effective amount of an inhibitor of a cellular gene to an individual to inhibit HIV infection.  
     
     
         9 . The method of  claim 8  in which the inhibitor down-regulates gene expression of a subunit of NADH dehydrogenase.  
     
     
         10 . The method of  claim 9  in which the inhibitor is mofarotene  
     
     
         11 . The method of  claim 8  in which the inhibitor interferes with enzyme activities.  
     
     
         12 . The method of  claim 11  in which the inhibitor is amytal.  
     
     
         13 . The method of  claim 8  in which the inhibitor is a 2-oxoglutarate dehydrogenase inhibitor.  
     
     
         14 . The method of  claim 8  in which the inhibitor is a pyruvate kinase inhibitor.  
     
     
         15 . The method of  claim 8  in which the inhibitor is a calnexin inhibitor.  
     
     
         16 . The method of  claim 8  in which the inhibitor is an ADP-ribosylation factor 3 inhibitor.