Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTRP4JT)

• DTT Name: Human immunodeficiency virus Rev messenger RNA (HIV rev mRNA)
• Synonyms: rev (mRNA); Regulator of expression of viral proteins (mRNA); Protein Rev (mRNA); Anti-repression transactivator (mRNA); ART/TRS (mRNA)
• Gene Name: HIV rev mRNA
• DTT Type: Clinical trial target; [1]
• BioChemical Class: mRNA target
• UniProt ID: REV_HV1H2
• TTD ID: T57364
• Sequence:
  MAGRSGDSDEELIRTVRLIKLLYQSNPPPNPEGTRQARRNRRRRWRERQRQIHSISERIL
  GTYLGRSAEPVPLQLPPLERLTLDCNEDCGTSGTQGVGSPQILVESPTVLESGTKE
• Function: These pre-mRNAs carry a recognition sequence called Rev responsive element (RRE) located in the env gene, that is not present in fully spliced viral mRNAs (early transcripts). This function is essential since most viral proteins are translated from unspliced or partially spliced pre-mRNAs which cannot exit the nucleus by the pathway used by fully processed cellular mRNAs. Rev itself is translated from a fully spliced mRNA that readily exits the nucleus. Rev's nuclear localization signal (NLS) binds directly to KPNB1/Importin beta-1 without previous binding to KPNA1/Importin alpha-1. KPNB1 binds to the GDP bound form of RAN (Ran-GDP) and targets Rev to the nucleus. In the nucleus, the conversion from Ran-GDP to Ran-GTP dissociates Rev from KPNB1 and allows Rev's binding to the RRE in viral pre-mRNAs. Rev multimerization on the RRE via cooperative assembly exposes its nuclear export signal (NES) to the surface. Rev can then form a complex with XPO1/CRM1 and Ran-GTP, leading to nuclear export of the complex. Conversion from Ran-GTP to Ran-GDP mediates dissociation of the Rev/RRE/XPO1/RAN complex, so that Rev can return to the nucleus for a subsequent round of export. Beside KPNB1, also seems to interact with TNPO1/Transportin-1, RANBP5/IPO5 and IPO7/RANBP7 for nuclear import. The nucleoporin-like HRB/RIP is an essential cofactor that probably indirectly interacts with Rev to release HIV RNAs from the perinuclear region to the cytoplasm. Escorts unspliced or incompletely spliced viral pre-mRNAs (late transcripts) out of the nucleus of infected cells.
• Reactome Pathway:
  Budding and maturation of HIV virion (R-HSA-162588)
  Integration of provirus (R-HSA-162592)
  Early Phase of HIV Life Cycle (R-HSA-162594)
  Minus-strand DNA synthesis (R-HSA-164516)
  Plus-strand DNA synthesis (R-HSA-164525)
  2-LTR circle formation (R-HSA-164843)
  Rev-mediated nuclear export of HIV RNA (R-HSA-165054)
  Binding and entry of HIV virion (R-HSA-173107)
  Assembly Of The HIV Virion (R-HSA-175474)
  Integration of viral DNA into host genomic DNA (R-HSA-175567)
  Autointegration results in viral DNA circles (R-HSA-177539)
  APOBEC3G mediated resistance to HIV-1 infection (R-HSA-180689)
  Nuclear import of Rev protein (R-HSA-180746)
  Vpr-mediated nuclear import of PICs (R-HSA-180910)
  Uncoating of the HIV Virion (R-HSA-162585)

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.