Abstract
After entry into the target cell, the human immunodeficiency virus type I (HIV) integrates into the host genome and becomes a proviral eukaryotic transcriptional unit. Transcriptional regulation of provirus gene expression is critical for HIV replication. Basal transcription from the integrated HIV promoter is very low in the absence of the HIV transactivator of transcription (Tat) protein and is solely dependent on cellular transcription factors. The 5' terminal region (+1 to +59) of all HIV mRNAs forms an identical stem-bulge-loop structure called the Transactivation Responsive (TAR) element. Once Tat is made, it binds to TAR and drastically activates transcription from the HIV LTR promoter. Mutations in either the Tat protein or TAR sequence usually affect HIV replication, indicating a strong requirement for their conservation. The necessity of the Tat-mediated transactivation cascade for robust HIV replication renders Tat one of the most desirable targets for transcriptional therapy against HIV replication. Screening based on inhibition of the Tat-TAR interaction has identified a number of potential compounds, but none of them are currently used as therapeutics, partly because these agents are not easily delivered for an efficient therapy, emphasizing the need for small molecule compounds. Here we will give an overview of the different strategies used to inhibit HIV transcription and review the current repertoire of small molecular weight compounds that target HIV transcription.
Highlights
Human immunodeficiency virus type I (HIV-1) is the causative agent of AcquiredImmunodeficiency Syndrome (AIDS) and affects more than 30 million people worldwide.Antiretroviral therapy (ART) used to treat the virus is based on triple or quadruple combinations of antiretrovirals (ARVs); effective and life prolonging, it does not eradicate human immunodeficiency virus type I (HIV) infection
We have recently found that Didehydro-Cortistatin A (dCA), an analogue of a natural steroidal alkaloid from a marine sponge, inhibits Tat-mediated trans-activation of the integrated provirus by binding to the Transactivation Responsive (TAR)-binding domain of Tat (Figure 2A,B) (Table 1) [146]. dCA represses transcriptional activation when transfected Tat or purified recombinant Tat is added to cells stably expressing the 5' long terminal repeat (LTR)
Screening for Tat/TAR inhibitors using, for example, electrophoretic mobility shift assay (EMSA) or filtration assays allowed the discovery of compounds with a good constant of inhibition and good affinity for TAR, if tested against
Summary
Immunodeficiency Syndrome (AIDS) and affects more than 30 million people worldwide. Antiretroviral therapy (ART) used to treat the virus is based on triple or quadruple combinations of antiretrovirals (ARVs); effective and life prolonging, it does not eradicate HIV infection. Ser of the RNAPII C-terminal domain (CTD) heptapeptide repeat, allowing interaction with additional factors involved in productive transcription (reviewed in [14]) The result of these post-translational modifications is synthesis of high levels of full-length viral transcripts. Before Tat is produced, low-level basal transcription from the viral promoter is initiated by cellular factors, such as NF-NB [34], Sp1 [35], TATA-binding protein [36] and RNAPII. A desirable Tat inhibitor should block Tat-mediated activation of the viral promoter without affecting its basal transcription, given the shared transcription factors of the HIV promoter and cellular genes. In prolonged treatment of chronically infected cells, a total shut-off of residual transcription can be achieved This reflects a unique feature of a Tat inhibitor, as it blocks transcription of the integrated provirus, contrary to the other anti-HIV drugs that only block de novo infection. An ideal Tat inhibitor would impact these other Tat mediated activities
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