Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTFP96H)

• DTT Name: Human immunodeficiency virus Tat messenger RNA (HIV tat mRNA)
• Synonyms: tat (mRNA); Transactivating regulatory protein (mRNA); Protein Tat (mRNA)
• Gene Name: HIV tat mRNA
• DTT Type: Clinical trial target; [1]
• BioChemical Class: mRNA target
• UniProt ID: TAT_HV1H2
• TTD ID: T60568
• Sequence:
  MEPVDPRLEPWKHPGSQPKTACTNCYCKKCCFHCQVCFITKALGISYGRKKRRQRRRAHQ
  NSQTHQASLSKQPTSQPRGDPTGPKE
• Function: Acts as a sequence-specific molecular adapter, directing components of the cellular transcription machinery to the viral RNA to promote processive transcription elongation by the RNA polymerase II (RNA pol II) complex, thereby increasing the level of full-length transcripts. In the absence of Tat, the RNA Pol II generates short or non-processive transcripts that terminate at approximately 60 bp from the initiation site. Tat associates with the CCNT1/cyclin-T1 component of the P-TEFb complex (CDK9 and CCNT1), which promotes RNA chain elongation. This binding increases Tat's affinity for a hairpin structure at the 5'-end of all nascent viral mRNAs referred to as the transactivation responsive RNA element (TAR RNA) and allows Tat/P-TEFb complex to bind cooperatively to TAR RNA. The CDK9 component of P-TEFb and other Tat-activated kinases hyperphosphorylate the C-terminus of RNA Pol II that becomes stabilized and much more processive. Other factors such as HTATSF1/Tat-SF1, SUPT5H/SPT5, and HTATIP2 are also important for Tat's function. Besides its effect on RNA Pol II processivity, Tat induces chromatin remodeling of proviral genes by recruiting the histone acetyltransferases (HATs) CREBBP, EP300 and PCAF to the chromatin. This also contributes to the increase in proviral transcription rate, especially when the provirus integrates in transcriptionally silent region of the host genome. To ensure maximal activation of the LTR, Tat mediates nuclear translocation of NF-kappa-B by interacting with host RELA. Through its interaction with host TBP, Tat may also modulate transcription initiation. Tat can reactivate a latently infected cell by penetrating in it and transactivating its LTR promoter. In the cytoplasm, Tat is thought to act as a translational activator of HIV-1 mRNAs. Nuclear transcriptional activator of viral gene expression, that is essential for viral transcription from the LTR promoter and replication.
• Reactome Pathway:
  Pausing and recovery of Tat-mediated HIV elongation (R-HSA-167238)
  Tat-mediated HIV elongation arrest and recovery (R-HSA-167243)
  Tat-mediated elongation of the HIV-1 transcript (R-HSA-167246)
  Interactions of Tat with host cellular proteins (R-HSA-176034)
  Formation of HIV-1 elongation complex containing HIV-1 Tat (R-HSA-167200)

Molecular Interaction Atlas (MIA) of This DTT

1 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
HGTV43	DM0LA6E	Human immunodeficiency virus-1 infection	1C62	Phase 2	[1]

References

• [1] Design and development of antisense drugs. Expert Opin. Drug Discov. 2008 3(10):1189-1207.