Method to limit immunodeficiency virus infection and compounds therefor

Abstract

Disclosed is a method to limit infection by an immunodeficiency virus. The method includes inhibiting an immunodeficiency virus protein which regulates apoptosis in cells. Also disclosed are methods to identify compounds that regulate cellular inhibitors of apoptosis in cells infected with an immunodeficiency virus and compounds identified thereby.

what is claimed is:  
     
         1 . A method to limit infection by an immunodeficiency virus, comprising inhibiting an immunodeficiency virus protein which regulates apoptosis in cells.  
     
     
         2 . The method of  claim 1 , wherein said immunodeficiency virus is HIV.  
     
     
         3 . The method of  claim 2 , wherein said HIV protein is selected from the group consisting of Vpr, Tat, Vif, Nef, Env, Gag and Vpu.  
     
     
         4 . The method of  claim 2 , wherein said HIV protein is Vpr.  
     
     
         5 . The method of  claim 1 , wherein said step of inhibiting comprises administering to a cell an inhibitor of an immunodeficiency virus protein which regulates apoptosis in cells.  
     
     
         6 . The method of  claim 5 , wherein said cell is a T cell.  
     
     
         7 . The method of  claim 6 , wherein said T cell is CD4 +  or CD8 + .  
     
     
         8 . The method of  claim 1 , further comprising inhibiting non-immunodeficiency virus induced cellular apoptosis of uninfected bystander cells.  
     
     
         9 . The method of  claim 8 , wherein said step of inhibiting non-immunodeficiency virus induced cellular apoptosis of uninfected bystander cells comprises regulating a compound selected from the group consisting of Lck, cAMP, Protein kinase A, cdc2, cysteine proteases, proteins of the TNF receptor family, p53, Ras, Raf, MEKK1, Jun kinases, bcl-2 and oxygen radicals.  
     
     
         10 . The method of  claim 1 , further comprising administering an inhibitor of immunodeficiency virus replication in immunodeficiency virus infected cells.  
     
     
         11 . The method of  claim 10 , wherein said immunodeficiency virus is HIV and said inhibitor is selected from the group consisting of nucleoside analogues, non-nucleoside analogues, protease inhibitors, chemokine receptor inhibitors, antibodies specific for gp160, antibodies specific for gp120, CD4-gp160 protein complexes and gp120-CD4 protein complexes.  
     
     
         12 . The method of  claim 1 , wherein said step of inhibiting is conducted in vivo.  
     
     
         13 . The method of  claim 1 , wherein said step of inhibiting is conducted ex vivo.  
     
     
         14 . The method of  claim 1 , wherein said step of inhibiting comprises systemically administering an inhibitor of an immunodeficiency virus protein which regulates apoptosis in cells.  
     
     
         15 . A method to identify a compound that regulates a cellular inhibitor of apoptosis in cells infected with an immunodeficiency virus, said method comprising: 
 (a) contacting a putative regulatory compound with cells infected with an immunodeficiency virus under conditions in which, in the absence of said compound, apoptosis of said cells is inhibited; and    (b) assessing the ability of said putative regulatory compound to regulate apoptosis in said cells, wherein a difference in the rate of apoptosis between infected cells contacted with said compound compared to infected cells not in contact with said compound indicates that said compound regulates a cellular inhibitor of apoptosis in cells infected with said immunodeficiency virus.    
     
     
         16 . The method of  claim 15 , wherein said immunodeficiency virus is HIV.  
     
     
         17 . The method of  claim 15 , wherein said cells comprise immunodeficiency virus infected T cells.  
     
     
         18 . The method of  claim 15 , wherein said T cells comprise CD4 +  or CD8 +  T cells.  
     
     
         19 . The method of  claim 15 , wherein said step of assessing comprises determining the ability of said putative regulatory compound to induce apoptosis in said cells.  
     
     
         20 . The method of  claim 19 , wherein said immunodeficiency virus is HIV and said step of assessing comprises determining the ability of said putative regulatory compound to inhibit an HIV protein selected from the group consisting of Vpr, Tat, Vif, Nef, Env, Gag and Vpu.  
     
     
         21 . The method of  claim 19 , wherein said immunodeficiency virus is HIV and said step of assessing comprises determining the ability of said putative regulatory compound to inhibit the HIV protein Vpr.  
     
     
         22 . The method of  claim 15 , wherein said step of assessing comprises a step selected from the group consisting of (1) determining the extent of a morphological change in a cell selected from the group consisting of progressive contraction of cell volume with the preservation of the integrity of cytoplasmic organelles and condensation of chromatin; (2) determining the extent of DNA cleavage; and (3) determining membrane permeability.  
     
     
         23 . A compound identified by the method of  claim 15 .  
     
     
         24 . A method to identify a compound that regulates a cellular inhibitor of apoptosis in cells infected with an immunodeficiency virus, said method comprising: 
 (a) contacting a putative regulatory compound with an immunodeficiency virus apoptosis inhibitor protein; and    (b) assessing the ability of said putative regulatory compound to regulate the activity of said immunodeficiency virus apoptosis inhibitor protein.    
     
     
         25 . The method of  claim 24 , wherein said immunodeficiency virus is HIV.  
     
     
         26 . The method of  claim 25 , wherein said HIV apoptosis inhibitor protein is selected from the group consisting of Vpr, Tat, Vif, Nef, Env, Gag and Vpu.  
     
     
         27 . The method of  claim 24 , wherein said HIV apoptosis inhibitor protein is Vpr protein.  
     
     
         28 . The method of  claim 24 , wherein said step of assessing comprises determining the ability of said putative regulatory compound to regulate an immunodeficiency virus apoptosis inhibitor protein by a mechanism selected from the group consisting of degrading said protein, inhibiting transcription of a gene encoding said protein, inhibiting translation of said protein, inhibiting activation of said protein, and inhibiting the interaction of said protein with another protein.