Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTF7I5O)

• DTT Name: Human immunodeficiency virus Rev protein (HIV rev)
• Synonyms: rev; Regulator of expression of viral proteins; Anti-repression transactivator; ART/TRS
• Gene Name: HIV rev
• DTT Type: Clinical trial target; [1]
• Related Disease: Human immunodeficiency virus disease [ICD-11: 1C60-1C62]
• UniProt ID: REV_HV1H2
• TTD ID: T00420
• Sequence:
  MAGRSGDSDEELIRTVRLIKLLYQSNPPPNPEGTRQARRNRRRRWRERQRQIHSISERIL
  GTYLGRSAEPVPLQLPPLERLTLDCNEDCGTSGTQGVGSPQILVESPTVLESGTKE
• Function: Escorts unspliced or incompletely spliced viral pre- mRNAs (late transcripts) out of the nucleus of infected cells. 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) bindsdirectly 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 conversionfrom 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. Interacts with DDX1; the interaction is necessary for proper subcellular localization of this protein.
• 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)
  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)
  Vpr-mediated nuclear import of PICs (R-HSA-180910)
  Uncoating of the HIV Virion (R-HSA-162585)

Molecular Interaction Atlas (MIA) of This DTT

2 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Ad35-GRIN/ENV	DMG82ZA	Human immunodeficiency virus infection	1C62	Phase 1	[2]
ATI-0917	DMT5Z84	Human immunodeficiency virus infection	1C62	Phase 1	[1]

References

• [1] Antiretroviral drugs in development. A report from HIV DART 2008: Frontiers in Drug Development for Antiretroviral Therapies, 9-12 December 2008, Rio Grande, Puerto Rico. Expert Opin Investig Drugs. 2009 Apr;18(4):549-53.
• [2] A phase I double blind, placebo-controlled, randomized study of a multigenic HIV-1 adenovirus subtype 35 vector vaccine in healthy uninfected adults. PLoS One. 2012;7(8):e41936.