Vpr is a
Human immunodeficiency virus
The human immunodeficiency viruses (HIV) are two species of ''Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the immun ...
gene and protein product.
Vpr stands for "Viral Protein R". Vpr, a 96
amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha ...
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.
Vpr also induces
G2 cell cycle arrest and apoptosis in proliferating cells, which can result in immune dysfunction.
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
Sequence homology is the biological homology between DNA, RNA, or protein sequences, defined in terms of shared ancestry in the evolutionary history of life. Two segments of DNA can have shared ancestry because of three phenomena: either a ...
)
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.
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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 repeat
The WD40 repeat (also known as the WD or beta-transducin repeat) is a short structural motif of approximately 40 amino acids, often terminating in a tryptophan-aspartic acid (W-D) dipeptide. Tandem copies of these repeats typically fold togeth ...
s.
VprBP acts as a substrate-recognition unit when associated with DNA damage-binding protein 1 (
DDB1
DNA damage-binding protein 1 is a protein that in humans is encoded by the ''DDB1'' gene.
Gene
The gene's position is on chromosome 11q12-q13.
Protein
The DDB1 gene encodes the large subunit of DNA damage-binding protein, a heterodimer compose ...
) as part of a
CUL4–DDB1
E3 ubiquitin ligase
A ubiquitin ligase (also called an E3 ubiquitin ligase) is a protein that recruits an E2 ubiquitin-conjugating enzyme that has been loaded with ubiquitin, recognizes a protein substrate, and assists or directly catalyzes the transfer of ubiquiti ...
complex.
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.
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.
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.
References
{{Viral proteins
Viral regulatory and accessory proteins
HIV/AIDS