tailieunhanh - Báo cáo y học: "Selective killing of human immunodeficiency virus infected cells by non-nucleoside reverse transcriptase inhibitor-induced activation of HIV proteas"

Tuyển tập các báo cáo nghiên cứu về y học được đăng trên tạp chí y học Respiratory Research cung cấp cho các bạn kiến thức về ngành y đề tài: Selective killing of human immunodeficiency virus infected cells by non-nucleoside reverse transcriptase inhibitor-induced activation of HIV protease. | Jochmans et al. Retrovirology 2010 7 89 http content 7 1 89 RETROVIROLOGY RESEARCH Open Access Selective killing of human immunodeficiency virus infected cells by non-nucleoside reverse transcriptase inhibitor-induced activation of HIV protease 13 2 1 1 2 1 DirkJochmans Maria Anders Inge Keuleers Liesbeth Smeulders Hans-Georg Krausslich Gunter Kraus Barbara Muller 2 Abstract Background Current antiretroviral therapy against human immunodeficiency virus HIV-1 reduces viral load and thereby prevents viral spread but it cannot eradicate proviral genomes from infected cells. Cells in immunological sanctuaries as well as cells producing low levels of virus apparently contribute to a reservoir that maintains HIV persistence in the presence of highly active antiretroviral therapy. Thus accelerated elimination of virus producing cells may represent a complementary strategy to control HIV infection. Here we sought to exploit HIV protease PR related cytotoxicity in order to develop a strategy for drug induced killing of HIV producing cells. PR processes the viral Gag and Gag-Pol polyproteins during virus maturation but is also implicated in killing of virus producing cells through off-target cleavage of host proteins. It has been observed previously that micromolar concentrations of certain non-nucleoside reverse transcriptase inhibitors NNRTIs can stimulate intracellular PR activity presumably by enhancing Gag-Pol dimerization. Results Using a newly developed cell-based assay we compared the degree of PR activation displayed by various NNRTIs. We identified inhibitors showing higher potency with respect to PR activation than previously described for NNRTIs with the most potent compounds resulting in 2-fold increase of the Gag processing signal at 250 nM. The degree of enhancement of intracellular Gag processing correlated with the compound s ability to enhance RT dimerization in a mammalian two-hybrid assay. Compounds were analyzed for their potential