Mitochondria and human immunodefiency virus type 1 transmission

Abstract

Methods described herein relate to mitochondria and their role in Human immunodeficiency virus type 1 (HIV-1) infection and cell-to-cell HIV-1 transmission and compositions and methods for modulating mitochondrial mediated cell-to-cell transmission of HIV-1. Methods for screening to identify inhibitors of mitochondrial mediated cell-to-cell transmission of HIV-1 are also envisioned herein.

What is claimed is: 
     
         1 . A method for screening to identify a compound for treating a subject infected with human immunodeficiency virus type 1 (HIV-1), the method comprising contacting HIV-1 infected cells and target cells with a candidate compound, wherein the target cells are susceptible to HIV-1 infection; and measuring cell-to-cell transmission of HIV-1 in the presence and absence of the candidate compound, wherein a reduction in cell-to-cell transmission of HIV-1 in the presence of the candidate compound relative to the absence of the candidate compound indicates that the candidate compound or agent is a therapeutic agent for treating the subject infected with HIV-1. 
     
     
         2 . The method of  claim 1 , wherein the candidate compound is a mitochondrial inhibitor. 
     
     
         3 . The method of  claim 2 , wherein the candidate compound is a mitochondrial inhibitor and a protease inhibitor. 
     
     
         4 . The method of  claim 1 , wherein the candidate compound is a modulator of cytoskeletal processes. 
     
     
         5 . The method of  claim 4 , wherein the cytoskeletal processes relate to actin or microtubule polymerization or depolymerization. 
     
     
         6 . The method of  claim 1 , wherein cell-to-cell transmission of HIV-1 is measured by tracking mitochondrial movement from the HIV-1 infected cells to the target cells. 
     
     
         7 . The method of  claim 6 , further comprising measuring virological synapse and syncytia formation. 
     
     
         8 . A method for screening to identify a compound that inhibits human immunodeficiency virus type 1 (HIV-1) uptake by mitochondria, the method comprising contacting HIV-1 infected cells and target cells with a candidate compound, wherein the target cells are susceptible to HIV-1 infection; and measuring uptake of HIV-1 by mitochondria in the target cells in the presence and absence of the candidate compound, wherein a reduction in uptake of HIV-1 by mitochondria in the target cells in the presence of the candidate compound relative to the absence of the candidate compound indicates that the candidate compound is an inhibitor of HIV-1 uptake by the mitochondria. 
     
     
         9 . The method of  claim 8 , wherein the candidate compound inhibits viral fusion. 
     
     
         10 . The method of  claim 9 , wherein the candidate compound is enfuvirtide (Fuzeon) or maraviroc (Selzentry). 
     
     
         11 . The method of  claim 8 , wherein the candidate compound inhibits activity of viral fusion protein gp41. 
     
     
         12 . The method of  claim 8 , wherein the candidate compound inhibits activity of mitochondrial fusion proteins. 
     
     
         13 . The method of  claim 8 , wherein measuring uptake of HIV-1 by mitochondria in the target cells is determined by isolating mitochondria from the target cells following contact with HIV-1 infected cells in the presence or absence of the candidate compound and determining and comparing infectivity of mitochondria isolated from target cells contacted with the candidate compound to infectivity of mitochondria isolated from target cells not contacted with the candidate compound, wherein decreased infectivity in the mitochondria isolated from target cells contacted with the candidate compound indicates that the candidate compound is an inhibitor of HIV-1 uptake by the mitochondria. 
     
     
         14 . A method for treating a subject infected with human immunodeficiency virus type 1 (HIV-1), the method comprising administering to the subject a mitochondrial inhibitor in a therapeutically effective amount, wherein the therapeutically effective amount is sufficient to reduce or inhibit cell-to-cell mediated transmission of HIV-1, thereby treating the subject infected HIV-1. 
     
     
         15 . The method of  claim 14 , wherein the mitochondrial inhibitor is ME-344, carbonyl cyanide m-chlorophenyl hydrazone (CCCP), antimycin A, or oligomycin. 
     
     
         16 . The method of  claim 14 , wherein the mitochondrial inhibitor is also a proteosome inhibitor. 
     
     
         17 . The method of  claim 16 , wherein the mitochondrial and proteosome inhibitor is bortezomib. 
     
     
         19 . The method of  claim 14 , further comprising treating the subject with a nucleoside analogue reverse transcriptase inhibitor and either of a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor.