Vpr Explained

Symbol:VPR
VPR
Pfam:PF00522
Interpro:IPR000012
Scop:1dsk
Tcdb:1.A.42

Vpr is a Human immunodeficiency virus gene and protein product. Vpr stands for "Viral Protein R". Vpr, a 96 amino acid 14-kDa protein, plays an important role in regulating nuclear import of the HIV-1 pre-integration complex, and is required for virus replication and enhanced gene expression from provirus in dividing or non-dividing cells such as T cells or macrophages.[1] Vpr also induces G2 cell cycle arrest and apoptosis in proliferating cells, which can result in immune dysfunction.[2] [3]

Vpr is also immunosuppressive due to its ability to sequester a proinflammatory transcriptional activator in the cytoplasm. HIV-2 contains both a Vpr protein and a related (by sequence homology) Vpx protein (Viral Protein X). Two functions of Vpr in HIV-1 are split between Vpr and Vpx in HIV-2, with the HIV-2 Vpr protein inducing cell cycle arrest and the Vpx protein required for nuclear import.__TOC__

Vpr-binding protein

Vpr-binding protein (VprBP) is a 1,507-amino-acid human protein that contains conserved domains, including YXXY repeats, the Lis homology motif, and WD40 repeats.[4] VprBP acts as a substrate-recognition unit when associated with DNA damage-binding protein 1 (DDB1) as part of a CUL4–DDB1 E3 ubiquitin ligase complex.[4] When bound to Vpr, VprBP allows Vpr to modulate the catalytic activity of the CUL4–DDB1 complex, inducing G2 cell cycle arrest in infected cells.[4]

VprBP also regulates p53-induced transcription and apoptotic pathways. p53 is an important tumor suppressor which induces either cell cycle arrest or apoptosis in response to DNA damage.[4]

In-vitro studies of Vpr

The lack of an in vitro cell culture system that demonstrated a deficit in replication upon infection with viruses in the absence of Vpr has led to some mystery in the function of Vpr. Recently, there has been experiments on monocyte-derived dendritic cells (MDDCs) using a novel in-vitro infection system. These infected human dendritic cells showed a slower rate of replication when deprived of the Vpr protein in HIV-1 cells. This replication difference occurred in a single round of infection. This was shown to be due to decreased transcriptional output from the integrated HIV viral genome. Using mutational analysis (biochemical identification of mutational changes in a nucleotide sequence), prevention of cell cycle progression into mitosis was shown to be required for LTR-mediated viral expression. These findings suggest that the evolutionarily secured G2 cell cycle arrest function of Vpr (Viral Protein R) is essential for HIV-1 replication. Furthermore, this innovative in-vitro culture system will allow researchers to address mechanisms underlying Vpr-mediated enhancement of HIV-1 replication.[5]

Notes and References

  1. Bhardwaj V, Singh A, Choudhary A, Dalavi R, Ralte L, Chawngthu RL, Senthil Kumar N, Vijay N, Chande A . 6 . HIV-1 Vpr induces ciTRAN to prevent transcriptional repression of the provirus . Science Advances . 9 . 36 . eadh9170 . September 2023 . 37672576 . 10482341 . 10.1126/sciadv.adh9170 .
  2. Bukrinsky M, Adzhubei A . Viral protein R of HIV-1 . Reviews in Medical Virology . 9 . 1 . 39–49 . 1999 . 10371671 . 10.1002/(SICI)1099-1654(199901/03)9:1<39::AID-RMV235>3.0.CO;2-3 . free .
  3. Muthumani K, Choo AY, Zong WX, Madesh M, Hwang DS, Premkumar A, Thieu KP, Emmanuel J, Kumar S, Thompson CB, Weiner DB . 6 . The HIV-1 Vpr and glucocorticoid receptor complex is a gain-of-function interaction that prevents the nuclear localization of PARP-1 . Nature Cell Biology . 8 . 2 . 170–179 . February 2006 . 16429131 . 3142937 . 10.1038/ncb1352 .
  4. Kim K, Heo K, Choi J, Jackson S, Kim H, Xiong Y, An W . Vpr-binding protein antagonizes p53-mediated transcription via direct interaction with H3 tail . Molecular and Cellular Biology . 32 . 4 . 783–796 . February 2012 . 22184063 . 3272969 . 10.1128/MCB.06037-11 .
  5. Miller CM, Akiyama H, Agosto LM, Emery A, Ettinger CR, Swanstrom RI, Henderson AJ, Gummuluru S . 6 . Virion-Associated Vpr Alleviates a Postintegration Block to HIV-1 Infection of Dendritic Cells . Journal of Virology . 91 . 13 . July 2017 . 28424288 . 5469257 . 10.1128/JVI.00051-17 .