Vpr

Last updated
VPR
PDB 1fi0 EBI.jpg
solution structure of hiv-1 vpr (13-33) peptide in micells
Identifiers
SymbolVPR
Pfam PF00522
InterPro IPR000012
SCOP2 1dsk / SCOPe / SUPFAM
TCDB 1.A.42
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary

Vpr is a Human immunodeficiency virus gene and protein product. [1] [2] 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. [3] Vpr also induces G2 cell cycle arrest and apoptosis in proliferating cells, which can result in immune dysfunction. [4] [5]

Contents

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.

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. [6] 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. [6] 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. [6]

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. [6]

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. [7]

Related Research Articles

<span class="mw-page-title-main">HIV</span> Human retrovirus, cause of AIDS

The human immunodeficiency viruses (HIV) are two species of Lentivirus that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive. Without treatment, average survival time after infection with HIV is estimated to be 9 to 11 years, depending on the HIV subtype.

<span class="mw-page-title-main">Retrovirus</span> Family of viruses

A retrovirus is a type of virus that inserts a DNA copy of its RNA genome into the DNA of a host cell that it invades, thus changing the genome of that cell. After invading a host cell's cytoplasm, the virus uses its own reverse transcriptase enzyme to produce DNA from its RNA genome, the reverse of the usual pattern, thus retro (backwards). The new DNA is then incorporated into the host cell genome by an integrase enzyme, at which point the retroviral DNA is referred to as a provirus. The host cell then treats the viral DNA as part of its own genome, transcribing and translating the viral genes along with the cell's own genes, producing the proteins required to assemble new copies of the virus. Many retroviruses cause serious diseases in humans, other mammals, and birds.

<span class="mw-page-title-main">Integrase</span> Class of enzymes

Retroviral integrase (IN) is an enzyme produced by a retrovirus that integrates—forms covalent links between—its genetic information into that of the host cell it infects. Retroviral INs are not to be confused with phage integrases (recombinases) used in biotechnology, such as λ phage integrase, as discussed in site-specific recombination.

The genome and proteins of HIV (human immunodeficiency virus) have been the subject of extensive research since the discovery of the virus in 1983. "In the search for the causative agent, it was initially believed that the virus was a form of the Human T-cell leukemia virus (HTLV), which was known at the time to affect the human immune system and cause certain leukemias. However, researchers at the Pasteur Institute in Paris isolated a previously unknown and genetically distinct retrovirus in patients with AIDS which was later named HIV." Each virion comprises a viral envelope and associated matrix enclosing a capsid, which itself encloses two copies of the single-stranded RNA genome and several enzymes. The discovery of the virus itself occurred two years following the report of the first major cases of AIDS-associated illnesses.

<span class="mw-page-title-main">Sp1 transcription factor</span> Protein-coding gene in the species Homo sapiens

Transcription factor Sp1, also known as specificity protein 1* is a protein that in humans is encoded by the SP1 gene.

<span class="mw-page-title-main">CCL5</span> Mammalian protein found in Homo sapiens

Chemokine ligand 5 is a protein which in humans is encoded by the CCL5 gene. The gene has been discovered in 1990 by in situ hybridisation and it is localised on 17q11.2-q12 chromosome. It is also known as RANTES. RANTES was first described by Dr. Tom Schall who named the protein, the original source of the name Rantes was from the Argentine movie Man Facing Southeast about an alien who shows up in a mental ward who was named Rantés, the rather clunky acronym was only made to fit the name.

Simian foamy virus (SFV) is a species of the genus Spumavirus that belongs to the family of Retroviridae. It has been identified in a wide variety of primates, including prosimians, New World and Old World monkeys, as well as apes, and each species has been shown to harbor a unique (species-specific) strain of SFV, including African green monkeys, baboons, macaques, and chimpanzees. As it is related to the more well-known retrovirus human immunodeficiency virus (HIV), its discovery in primates has led to some speculation that HIV may have been spread to the human species in Africa through contact with blood from apes, monkeys, and other primates, most likely through bushmeat-hunting practices.

<span class="mw-page-title-main">Long terminal repeat</span>

A long terminal repeat (LTR) is a pair of identical sequences of DNA, several hundred base pairs long, which occur in eukaryotic genomes on either end of a series of genes or pseudogenes that form a retrotransposon or an endogenous retrovirus or a retroviral provirus. All retroviral genomes are flanked by LTRs, while there are some retrotransposons without LTRs. Typically, an element flanked by a pair of LTRs will encode a reverse transcriptase and an integrase, allowing the element to be copied and inserted at a different location of the genome. Copies of such an LTR-flanked element can often be found hundreds or thousands of times in a genome. LTR retrotransposons comprise about 8% of the human genome.

Visna-maedi virus from the genus Lentivirus and subfamily Orthoretrovirinae, is a retrovirus that causes encephalitis and chronic pneumonitis in sheep. It is known as visna when found in the brain, and maedi when infecting the lungs. Lifelong, persistent infections in sheep occur in the lungs, lymph nodes, spleen, joints, central nervous system, and mammary glands; The condition is sometimes known as ovine progressive pneumonia (OPP), particularly in the United States, or Montana sheep disease. White blood cells of the monocyte/macrophage lineage are the main target of the virus.

<span class="mw-page-title-main">Antibody-dependent enhancement</span> Antibodies rarely making an infection worse instead of better

Antibody-dependent enhancement (ADE), sometimes less precisely called immune enhancement or disease enhancement, is a phenomenon in which binding of a virus to suboptimal antibodies enhances its entry into host cells, followed by its replication. The suboptimal antibodies can result from natural infection or from vaccination. ADE may cause enhanced respiratory disease, but is not limited to respiratory disease. It has been observed in HIV, RSV virus and Dengue virus and is monitored for in vaccine development.

<span class="mw-page-title-main">Importin subunit alpha-6</span> Protein-coding gene in the species Homo sapiens

Importin subunit alpha-6 is a protein that in humans is encoded by the KPNA5 gene.

<span class="mw-page-title-main">CUL4A</span> Protein-coding gene in the species Homo sapiens

Cullin-4A is a protein that in humans is encoded by the CUL4A gene. CUL4A belongs to the cullin family of ubiquitin ligase proteins and is highly homologous to the CUL4B protein. CUL4A regulates numerous key processes such as DNA repair, chromatin remodeling, spermatogenesis, haematopoiesis and the mitotic cell cycle. As a result, CUL4A has been implicated in several cancers and the pathogenesis of certain viruses including HIV. A component of a CUL4A complex, Cereblon, was discovered to be a major target of the teratogenic agent thalidomide.

<span class="mw-page-title-main">Cyclin B2</span> Protein-coding gene in the species Homo sapiens

G2/mitotic-specific cyclin-B2 is a protein that in humans is encoded by the CCNB2 gene.

<span class="mw-page-title-main">PPP2R5B</span> Protein-coding gene in the species Homo sapiens

Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit beta isoform is an enzyme that in humans is encoded by the PPP2R5B gene.

<span class="mw-page-title-main">PPP2R5E</span> Protein-coding gene in the species Homo sapiens

Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit epsilon isoform is an enzyme that in humans is encoded by the PPP2R5E gene.

<span class="mw-page-title-main">SAMHD1</span>

SAM domain and HD domain-containing protein 1 is a protein that in humans is encoded by the SAMHD1 gene. SAMHD1 is a cellular enzyme, responsible for blocking replication of HIV in dendritic cells, macrophages, monocytes and resting CD4+ T lymphocytes. It is an enzyme that exhibits phosphohydrolase activity, converting deoxynucleoside triphosphates (dNTPs) to inorganic phosphate (iPPP) and a 2'-deoxynucleoside (i.e. deoxynucleosides without a phosphate group). In doing so, SAMHD1 depletes the pool of dNTPs available to a reverse transcriptase for viral cDNA synthesis and thus prevents viral replication. SAMHD1 has also shown nuclease activity. Although a ribonuclease activity was described to be required for HIV-1 restriction, recent data confirmed that SAMHD1-mediated HIV-1 restriction in cells does not involve ribonuclease activity.

<span class="mw-page-title-main">VPRBP</span> Protein-coding gene in the species Homo sapiens

Protein VPRBP is a protein that in humans is encoded by the VPRBP gene.

<span class="mw-page-title-main">HIV integration</span>

AIDS is caused by the human immunodeficiency virus (HIV). Individuals with HIV have what is referred to as a "HIV infection". When infected semen, vaginal secretions, or blood come in contact with the mucous membranes or broken skin of an uninfected person, HIV may be transferred to the uninfected person, causing another infection. Additionally, HIV can also be passed from infected pregnant women to their uninfected baby during pregnancy and/or delivery, or via breastfeeding. As a result of HIV infection, a portion of these individuals will progress and go on to develop clinically significant AIDS.

<span class="mw-page-title-main">IFNA16</span> Protein-coding gene in the species Homo sapiens

Interferon alpha-16, also known as IFN-alpha-16, is a protein that in humans is encoded by theIFNA16 gene.

Vpx is a virion-associated protein encoded by human immunodeficiency virus type 2 HIV-2 and most simian immunodeficiency virus (SIV) strains, but that is absent from HIV-1. It is similar in structure to the protein Vpr that is carried by SIV and HIV-2 as well as HIV-1. Vpx is one of five accessory proteins carried by lentiviruses that enhances viral replication by inhibiting host antiviral factors.

References

  1. Vpr+Gene+Products,+Human+Immunodeficiency+Virus at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
  2. Genes,+Vpr at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
  3. Bhardwaj, Vipin; Singh, Aman; Dalavi, Rishikesh; Ralte, Lalchhanhima; Chawngthu, Richard L.; Kumar, Nachimuthu Senthil; Vijay, Nagarjun; Chande, Ajit (2022-11-04). "HIV-1 Vpr induces ciTRAN to prevent transcriptional silencing of the provirus": 2022.11.04.515166. doi:10.1101/2022.11.04.515166v1.{{cite journal}}: Cite journal requires |journal= (help)
  4. Bukrinsky M, Adzhubei A (1999). "Viral protein R of HIV-1". Reviews in Medical Virology. 9 (1): 39–49. doi: 10.1002/(SICI)1099-1654(199901/03)9:1<39::AID-RMV235>3.0.CO;2-3 . PMID   10371671.
  5. Muthumani K, Choo AY, Zong WX, Madesh M, Hwang DS, Premkumar A, Thieu KP, Emmanuel J, Kumar S, Thompson CB, Weiner DB (February 2006). "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): 170–9. doi:10.1038/ncb1352. PMC   3142937 . PMID   16429131.
  6. 1 2 3 4 Kim K, Heo K, Choi J, Jackson S, Kim H, Xiong Y, An W (February 2012). "Vpr-binding protein antagonizes p53-mediated transcription via direct interaction with H3 tail". Molecular and Cellular Biology. 32 (4): 783–96. doi:10.1128/MCB.06037-11. PMC   3272969 . PMID   22184063.
  7. Miller CM, Akiyama H, Agosto LM, Emery A, Ettinger CR, Swanstrom RI, Henderson AJ, Gummuluru S (July 2017). "Virion-Associated Vpr Alleviates a Postintegration Block to HIV-1 Infection of Dendritic Cells". Journal of Virology. 91 (13). doi:10.1128/JVI.00051-17. PMC   5469257 . PMID   28424288.