Compositions and methods for reactivating latent viral infections

Abstract

The present invention provides compositions comprising ingenol-3-angelate (PEP005) and one or more additional latency reactivation agents. The present invention also provides methods for reactivating a latent virus in a subject infected with the virus, the method comprising administering to the subject an effective amount of ingenol-3-angelate (PEP005) alone or in combination with one or more additional latency reactivation agents. In particular embodiments, the combination of compounds advantageously provides a synergistic effect at inducing reactivation of a latent virus such as HIV.

1 . A composition comprising ingenol-3-angelate (PEP005) and one or more additional latency reactivation agents. 
     
     
         2 . The composition of  claim 1 , wherein the ingenol-3-angelate (PEP005) is present in an amount effective to enhance a therapeutic benefit of the one or more additional latency reactivation agents. 
     
     
         3 . The composition of  claim 2 , wherein the therapeutic benefit comprises reactivation of a latent virus in a subject infected with the virus. 
     
     
         4 . The composition of  claim 3 , wherein the virus is selected from the group consisting of a human immunodeficiency virus (HIV), a cytomegalovirus (CMV), and an adenovirus. 
     
     
         5 . The composition of  claim 1 , wherein the one or more additional latency reactivation agents is selected from the group consisting of a positive transcription elongation factor b activator, a histone methyltransferase (HMT) inhibitor, a histone deacetylase (HDAC) inhibitor, a DNA methyltransferase inhibitor, an NF-κB activator, an Akt/HEXIM-1 modulator, a Jak/Stat pathway modulator, a phorbol ester, a macrolide lactone, a diacylglycerol (DAG) lactone, a protein kinase C (PKC) activator, and combinations thereof. 
     
     
         6 . The composition of  claim 5 , wherein the positive transcription elongation factor b activator is selected from the group consisting of JQ1, hexamethylene bisacetamide (HMBA), and combinations thereof. 
     
     
         7 . The composition of  claim 5 , wherein the histone methyltransferase (HMT) inhibitor is selected from the group consisting of GSK343, BIX01294, chaetocin, 3-deazaneplanocin A (DZNep), and combinations thereof. 
     
     
         8 . The composition of  claim 5 , wherein the histone deacetylase (HDAC) inhibitor is selected from the group consisting of vorinostat (suberanilohydroxamic acid; SAHA), suberoyl bis-hydroxamic acid (SBHA), trichostatin A (TsA), scriptaid, oxamflatin, givinostat (ITF2357), belinostat (PXD101), droxinostat, CG05/CG06, valproic acid (VPA), sodium butyrate, apicidin, and combinations thereof. 
     
     
         9 . The composition of  claim 1 , wherein the one or more additional latency reactivation agents is a positive transcription elongation factor b activator. 
     
     
         10 . The composition of  claim 9 , wherein the positive transcription elongation factor b activator is JQ1. 
     
     
         11 . The composition of  claim 1 , wherein the one or more additional latency reactivation agents is a histone methyltransferase (HMT) inhibitor. 
     
     
         12 . The composition of  claim 11 , wherein the histone methyltransferase (HMT) inhibitor is GSK343. 
     
     
         13 . The composition of  claim 1 , wherein the one or more additional latency reactivation agents is a histone deacetylase (HDAC) inhibitor. 
     
     
         14 . The composition of  claim 13 , wherein the histone deacetylase (HDAC) inhibitor is SAHA. 
     
     
         15 . The composition of  claim 1 , further comprising a viral therapy vaccine. 
     
     
         16 . The composition of  claim 1 , further comprising a pharmaceutically acceptable excipient or diluent. 
     
     
         17 . A method for reactivating a latent virus in a subject infected with the virus, the method comprising administering to the subject an effective amount of ingenol-3-angelate (PEP005). 
     
     
         18 . The method of  claim 17 , wherein the effective amount of the ingenol-3-angelate (PEP005) is an amount that is capable of inducing RNA transcription from the latent virus in an infected cell from the subject. 
     
     
         19 . The method of  claim 18 , wherein the infected cell is a CD4+ T cell. 
     
     
         20 . The method of  claim 17 , wherein the effective amount of the ingenol-3-angelate (PEP005) is an amount that displays low to minimal cytotoxicity without inducing global T cell activation. 
     
     
         21 - 48 . (canceled)