Blocking HIV-1 Replication via Targeting the Tatmediated Transcriptional Machinery

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HIV-1 infection can be effectively controlled by highly active antiretroviral therapy (HAART), which improves the quality of lives of infected individuals, but fails to completely eradicate the virus, even after decades of treatment. This issue, together with the emergence of multi-drug-resistant viruses, clearly underscores the continuing need to find novel agents able to target vulnerable steps in the viral replication cycle. HIV transcriptional regulation is a crucial step required to re-initiate viral replication from post-integration latency after interruption of therapy and to keep the virus in circulation. In this step, the viral protein Tat plays a central role by dramatically increasing the production of elongated transcripts through its unique interaction with the viral TAR RNA and the cellular cofactor P-TEFb, together with a myriad of other host factors which are recruited to the viral promoter to ensure efficient transcription. The transcriptional machinery, involving an intricate interplay of many viral and cellular components, offers a plethora of potential therapeutic targets that have not yet been exploited by any of the antiretroviral drugs used in therapy.