BK virus

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BK virus
Decoy cell cytology.png
Cytology of a polyomavirus infected cell, using Papanicolaou stain. The high nuclear to cytoplasmic ratio makes it resemble cancer (thus the name "decoy cell") but the inclusion body reveals its viral pathophysiology.
Specialty Infectious disease

The BK virus, also known as Human polyomavirus 1, is a member of the polyomavirus family. Past infection with the BK virus is widespread, [1] but significant consequences of infection are uncommon, with the exception of the immunocompromised and the immunosuppressed. BK virus is an abbreviation of the name of the first patient, from whom the virus was isolated in 1971. This patient - a male - was then 39 years old, who had developed constriction of the ureter after a renal transplant. [2]

Contents

Signs and symptoms

The BK virus rarely causes disease but is typically associated with patients who have had a kidney transplant; many people who are infected with this virus are asymptomatic. If symptoms do appear, they tend to be mild: respiratory infection or fever. These are known as primary BK infections. Although without any clinical symptoms, footprints of BK virus have been detected in specimens from females affected by spontaneous abortion. [3] Serum antibodies against BK virus have also been found in spontaneous abortion affected women as well as in women who underwent voluntary interruption of pregnancy. [4]

The virus then disseminates to the kidneys and urinary tract where it persists for the life of the individual. It is thought that up to 80% of the population contains a latent form of this virus, which remains latent until the body undergoes some form of immunosuppression. Typically, this is in the setting of kidney transplantation or multi-organ transplantation. [5] Presentation in these immunocompromised individuals is much more severe. Clinical manifestations include renal dysfunction (seen by a progressive rise in serum creatinine), and an abnormal urinalysis revealing renal tubular cells and inflammatory cells.[ citation needed ]

Cause

Human polyomavirus 1
Virus classification OOjs UI icon edit-ltr.svg
(unranked): Virus
Realm: Monodnaviria
Kingdom: Shotokuvirae
Phylum: Cossaviricota
Class: Papovaviricetes
Order: Sepolyvirales
Family: Polyomaviridae
Genus: Betapolyomavirus
Species:
Human polyomavirus 1
Synonyms
  • BK polyomavirus
  • BK virus

Transmission

It is not known how this virus is transmitted, except that it spreads from person to person, and not from an animal source. It has been suggested that this virus may be transmitted through respiratory fluids or urine, since infected individuals periodically excrete virus in the urine. A survey of 400 healthy blood donors was reported as showing that 82% were positive for IgG against BK virus. [6]

Risk factors

In some renal transplant patients, the necessary use of immunosuppressive drugs has the side-effect of allowing the virus to replicate within the graft, a disease called BK nephropathy. [7] From 1–10% of renal transplant patients progress to BK virus associated nephropathy (BKVAN) and up to 80% of these patients lose their grafts. The onset of nephritis can occur as early as several days post-transplant to as late as 5 years.[ citation needed ]

It is also associated with ureteral stenosis and interstitial nephritis. In bone marrow transplant recipients it is notable as a cause for hemorrhagic cystitis.[ citation needed ]

BK viremia load > 185 000 copies/ml at the time of first positive BKV diagnosis – to be the strongest predictor for BKVAN (97% specificity and 75% sensitivity). In addition the BKV peak viral loads in blood reaching 223 000 copies/ml at any time was found to be predictive for BKVAN (91% specificity and 88% sensitivity) . [8]

Diagnosis

Micrograph showing a polyomavirus infected cell - large (blue) cell below-center-left. Urine cytology specimen. Polyomavirus.jpg
Micrograph showing a polyomavirus infected cell – large (blue) cell below-center-left. Urine cytology specimen.

This virus can be diagnosed by a BKV blood test or a urine test for decoy cells, in addition to carrying out a biopsy in the kidneys. PCR techniques are often carried out to identify the virus. [9]

Treatment

The cornerstone of therapy is reduction in immunosuppression. A recent surge in BKVAN correlates with use of potent immunosuppressant drugs, such as tacrolimus and mycophenolate mofetil (MMF). Studies have not shown any correlation between BKVAN and a single immunosuppressive agent but rather the overall immunosuppressive load.[ citation needed ]

  1. Withdrawal of MMF or tacrolimus
  2. Replacement of tacrolimus by cyclosporine
  3. Overall reduction of immunosuppressive load
  4. Some cyclosporine trough levels reported to be reduced to 100–150 ng/ml and tacrolimus levels reduced to 3–5 ng/ml

Other therapeutic options include Leflunomide, Cidofovir, IVIG, and the fluoroquinolones. Leflunomide, a pyrimidine synthesis inhibitor is now generally accepted as the second treatment option behind reduction of immunosuppression.[ citation needed ]

Leflunomide in BKVAN

The rationale behind using leflunomide in BKVAN comes from its combined immunosuppressive and antiviral properties. Two studies consisting of 26 and 17 patients who developed BKVAN on a three-drug regimen of tacrolimus, MMF, and steroids had their MMF replaced with leflunomide 20–60 mg daily. 84 and 88% of patients, respectively had clearance or a progressive reduction in viral load and a stabilization or improvement of graft function (7).[ citation needed ] In a study conducted by Teschner et al. in 2009, 12/13 patients who had their MMF exchanged with leflunomide cleared the virus by 109 days. In a case series, there was improvement or stabilization in 23/26 patients with BKVAN after switching MMF to leflunomide.[ citation needed ]

There are no dosing guidelines for leflunomide in BKVAN. Patient to patient variability has made dosing and monitoring of leflunomide extremely difficult.

Other treatment options

History

The BK virus was first isolated in 1971 from the urine of a renal transplant patient, initials B.K. [10] The BK virus is similar to another virus called the JC virus (JCV), since their genomes share 75% sequence similarity. Both of these viruses can be identified and differentiated from each other by carrying out serological tests using specific antibodies or by using a PCR-based genotyping approach.[ citation needed ]

Virology

Virus structure

Similarly to JC virus and SV40, BK virus has a small, non-enveloped, icosahedral capsid with a diameter of 45–50 nm. [11] The capsid is made up of viral proteins VP1, VP2, and VP3. The capsid proteins have T=7 arrangement. The icosahedral structure contains 72 pentamers of the major capsid protein VP1, 360 molecules in total. Each penton is bound the minor capsid proteins VP2 or VP3 on the inside of the virus while VP1 protein shell is on the outside. [12]

Genome

BKV genome is approximately 5,000bp long and can vary depending on non-coding control region.The genome is compacted by cellular histone proteins H2A, H2B, H3 and H4, forming a structure termed "minichromosome" due to being chromatin-like.

The genome is divided into early coding region, late coding region and non-coding control region (NCCR). Transcription from ORI site produces mRNA coding the early, functional proteins, known as small and large T antigens, (sTAg and LTAg). These proteins function in viral DNA replication and cell cycle progression, by promoting S phase in the host cell. The late transcript codes for structural proteins VP1, VP2, and VP3 and functional protein known as agnoprotein. [12]

Archetype and rearranged virus forms

Different viral forms based on NCCR sequence variant (archetype or rearranged). The NCCR contains O,P,Q,R,S blocks and their variations. Non-coding control region blocks of BK polyomavirus.png
Different viral forms based on NCCR sequence variant (archetype or rearranged). The NCCR contains O,P,Q,R,S blocks and their variations.

Non-coding control region (NCCR) is prone to variation by DNA rearrangements. The most common and transmissible (wild-type) form based on NCCR region is called Archetype and has five sequence blocks (O-P-Q-R-S). Rearranged virus can have deletions, insertions or other types of mutations that lead to variation in the P-Q-R-S blocks. [13] Some viruses can have deletions and insertions of several blocks, as is the case with the Dunlop strain (O-P-P-P-S). [12]

Rearrangement of archetype frequently arises in cell cultures and in patients. Certain rearranged variants can lead to much higher viral replication compared to archetype. [14] This is thought to be due to enhanced promoter activity and high levels of early mRNA expression. [15]

Genotypes and subtypes

Based on DNA sequence variation, BKV is categorized into four genotypes (I, II, III, IV) which are further divided into subtypes (Ia, Ib1, Ib2, Ic, and IVa1, IVa2, IVb1, IVb2, IVc1, IVc2). [13] Genotype I is found wordwide, while other genotypes are geographically distributed. [16]

Replication cycle

BK virus enters the host cells by caveolae-mediated endocytic pathway. [12] The viral protein VP1 binds to α2-8-linked disialic acid motifs on gangliosides GD1b and GT1b on cell membranes. After caveola-mediated endocytosis, the virus capsid is uncoated while VP2 and VP3 mediate the entry of BKV into the nucleus. BKV genome is episomal and does not integrate into host DNA under normal conditions.

The early coding region is transcribed first to make functional proteins LTAg and sTAg. These proteins accumulate in the nucleus and facilitate the replication of viral DNA. LTAg binds to the late coding region, acting as a helicase to facilitate the transcription of proteins coded on the late region. The capsid proteins VP1-3 are produced in the cytoplasm and later recruited to the nucleus in order to assemble new virus particles.

One additional transmission and uptake route between cells is via extracellular vesicles. The virus can transfer viral components or even infectious particles between cells using cellular secretory system by utilizing extracellular vesicles. [14]

Tissue tropism

BK virus has a wide spectrum of tissue and cell type tropism. The virus is detected in urinary tract system, salivary gland cells, peripheral blood leukocytes, pancreatic cells, vascular endothelial cells. [17] BKV has been identified in upper respiratory tract and tonsils as well as in fetus cells. [12]

Viral latency

BK virus infection is self-limiting and is known to establish lifelong latent infection in the urinary system. The mechanism of how the virus establishes latency is not fully understood. Therefore, it is not known if BKV stays latent in the cells or maintains low level replication with persistent infection. The viral ability to establish latency in renal tubule or urothelium cells in healthy hosts can be detrimental in immunocompromised host due to viral reactivation. Viral reactivation is common in kidney transplant recipients, hematopoietic stem cell transplantation recipients and HIV/AIDS patients. [12]

Most often, the persistent infection is explained by innate and adaptive immune regulation. Another mechanism on how the virus can be self-limiting is by using microRNA and targeting the DNA sequence of the functional protein Large T antigen. This miRNA is transcribed during the late viral phase and is believed to effectively limit the archetype virus form. [14] Additionally, both agnoprotein and small T antigen can have a role in latency by impairing the innate immune signalling. Specifically, agnoprotein is known to impair IRF3 nuclear translocation and induce mitochondrial fragementation. Small T antigen can interact with a cellular enzyme protein phosphatase 2A which interferes with cell cycle progression. [15]

See also

Related Research Articles

<i>Polyomaviridae</i> Family of viruses

Polyomaviridae is a family of viruses whose natural hosts are primarily mammals and birds. As of 2024, there are eight recognized genera. 14 species are known to infect humans, while others, such as Simian Virus 40, have been identified in humans to a lesser extent. Most of these viruses are very common and typically asymptomatic in most human populations studied. BK virus is associated with nephropathy in renal transplant and non-renal solid organ transplant patients, JC virus with progressive multifocal leukoencephalopathy, and Merkel cell virus with Merkel cell cancer.

<span class="mw-page-title-main">SV40</span> Species of virus

SV40 is an abbreviation for simian vacuolating virus 40 or simian virus 40, a polyomavirus that is found in both monkeys and humans. Like other polyomaviruses, SV40 is a DNA virus that sometimes causes tumors in animals, but most often persists as a latent infection. SV40 has been widely studied as a model eukaryotic virus, leading to many early discoveries in eukaryotic DNA replication and transcription.

<i>Human polyomavirus 2</i> Species of virus

Human polyomavirus 2, commonly referred to as the JC virus or John Cunningham virus, is a type of human polyomavirus. It was identified by electron microscopy in 1965 by ZuRhein and Chou, and by Silverman and Rubinstein. It was later isolated in culture and named using the initials of a patient by the name of John Cunningham from whom it was isolated and had developed progressive multifocal leukoencephalopathy (PML). The virus causes leukoencephalopathy and other diseases only in cases of immunodeficiency, as in AIDS or during treatment with immunosuppressive drugs.

<span class="mw-page-title-main">Leflunomide</span> Chemical compound

Leflunomide, sold under the brand name Arava among others, is an immunosuppressive disease-modifying antirheumatic drug (DMARD), used in active moderate-to-severe rheumatoid arthritis and psoriatic arthritis. It is a pyrimidine synthesis inhibitor that works by inhibiting dihydroorotate dehydrogenase.

<span class="mw-page-title-main">Decoy cells</span> Virally infected epithelial cells found in urine

Decoy cells are virally infected epithelial cells that can be found in the urine. Decoy cells owe their name to their strong resemblance to cancer cells, and may as such confuse the diagnosis of either viral infection or urothelial malignancy. During 1950s, cytotechnologist Andrew Ricci observed cells mimicking cancer cells by they were not, in a group of persons working in some kinds of industries - they were referred to as “decoy cells”, analogous to “decoy ducks” used in hunting wild ducks, by Andrew Ricci, a cytotechnologist working renown cytopathologist Dr. Leopold G. Koss.

Merkel cell polyomavirus was first described in January 2008 in Pittsburgh, Pennsylvania. It was the first example of a human viral pathogen discovered using unbiased metagenomic next-generation sequencing with a technique called digital transcriptome subtraction. MCV is one of seven currently known human oncoviruses. It is suspected to cause the majority of cases of Merkel cell carcinoma, a rare but aggressive form of skin cancer. Approximately 80% of Merkel cell carcinoma (MCC) tumors have been found to be infected with MCV. MCV appears to be a common—if not universal—infection of older children and adults. It is found in respiratory secretions, suggesting that it might be transmitted via a respiratory route. However, it has also been found elsewhere, such as in shedded healthy skin and gastrointestinal tract tissues, thus its precise mode of transmission remains unknown. In addition, recent studies suggest that this virus may latently infect the human sera and peripheral blood mononuclear cells.

<span class="mw-page-title-main">Trichodysplasia spinulosa</span> Medical condition

Trichodysplasia spinulosa is a rare cutaneous condition that has been described almost exclusively in immunocompromised patients, usually organ transplant recipients, on regimens of immunosuppressive drugs. As of early 2016, a total of 32 cases had been reported in the medical literature. Despite its rarity, TS is believed to be underdiagnosed, and the growing population of patients on immunosuppressive drug regimens suggests its incidence may rise. TS has been described as an emerging infectious disease.

Trichodysplasia spinulosa polyomavirus is a member virus of Human polyomavirus 8 that infects human hosts. First discovered in 2010, TSPyV is associated with Trichodysplasia spinulosa, a rare skin disease only seen in immunocompromised patients. The virus causes hyperproliferation and enlargement of hair follicles by modulating PP2A protein phosphatase signaling pathways. TSPyV was the eighth human polyomavirus to be discovered, and one of four associated with human disease, out of 13 human polyomaviruses known as of the 2015 update to polyomavirus taxonomy released by the International Committee on Taxonomy of Viruses.

<span class="mw-page-title-main">Murine polyomavirus</span> Species of virus

Murine polyomavirus is an unenveloped double-stranded DNA virus of the polyomavirus family. The first member of the family discovered, it was originally identified by accident in the 1950s. A component of mouse leukemia extract capable of causing tumors, particularly in the parotid gland, in newborn mice was reported by Ludwik Gross in 1953 and identified as a virus by Sarah Stewart and Bernice Eddy at the National Cancer Institute, after whom it was once called "SE polyoma". Stewart and Eddy would go on to study related polyomaviruses such as SV40 that infect primates, including humans. These discoveries were widely reported at the time and formed the early stages of understanding of oncoviruses.

<span class="mw-page-title-main">Major capsid protein VP1</span>

Major capsid protein VP1 is a viral protein that is the main component of the polyomavirus capsid. VP1 monomers are generally around 350 amino acids long and are capable of self-assembly into an icosahedral structure consisting of 360 VP1 molecules organized into 72 pentamers. VP1 molecules possess a surface binding site that interacts with sialic acids attached to glycans, including some gangliosides, on the surfaces of cells to initiate the process of viral infection. The VP1 protein, along with capsid components VP2 and VP3, is expressed from the "late region" of the circular viral genome.

Hamster polyomavirus is an unenveloped double-stranded DNA virus of the polyomavirus family whose natural host is the hamster. It was originally described in 1967 by Arnold Graffi as a cause of epithelioma in Syrian hamsters.

WU polyomavirus is a virus of the family Polyomaviridae. It was discovered in 2007 in samples of human respiratory secretions, originally from a child patient in Australia who presented with clinical signs of pneumonia and in whom other common respiratory viruses were not detected. Follow-up studies identified the presence of WU virus in respiratory secretion samples from patients in Australia and the United States, suggesting that, like other human polyomaviruses, WU virus is widely distributed.

KI polyomavirus is a virus of the family Polyomaviridae. It was discovered in 2007 in stored samples of human respiratory secretions collected by the Karolinska Institute, after which the virus is named.

<span class="mw-page-title-main">Agnoprotein</span> Viral protein found in some polyomaviruses

Agnoprotein is a protein expressed by some members of the polyomavirus family from a gene called the agnogene. Polyomaviruses in which it occurs include two human polyomaviruses associated with disease, BK virus and JC virus, as well as the simian polyomavirus SV40.

MW polyomavirus is a virus of the polyomavirus family that infects human hosts. It was discovered in 2012 and reported independently by several research groups. It has been identified mostly in stool samples from children and has been detected in a variety of geographic locations.

STL polyomavirus is a virus of the polyomavirus family that infects human hosts. It was first reported in 2013 and is most closely related to MW polyomavirus. It has been identified mostly in stool samples from children and has been detected in a variety of geographic locations.

New Jersey polyomavirus is a virus of the polyomavirus family that infects human hosts. It was first identified in 2014 in a pancreatic transplant patient in New Jersey. It is the 13th and most recent human polyomavirus to be described.

<span class="mw-page-title-main">Large tumor antigen</span>

The large tumor antigen is a protein encoded in the genomes of polyomaviruses, which are small double-stranded DNA viruses. LTag is expressed early in the infectious cycle and is essential for viral proliferation. Containing four well-conserved protein domains as well as several intrinsically disordered regions, LTag is a fairly large multifunctional protein; in most polyomaviruses, it ranges from around 600-800 amino acids in length. LTag has two primary functions, both related to replication of the viral genome: it unwinds the virus's DNA to prepare it for replication, and it interacts with proteins in the host cell to dysregulate the cell cycle so that the host's DNA replication machinery can be used to replicate the virus's genome. Some polyomavirus LTag proteins - most notably the well-studied SV40 large tumor antigen from the SV40 virus - are oncoproteins that can induce neoplastic transformation in the host cell.

<span class="mw-page-title-main">Small tumor antigen</span>

The small tumor antigen is a protein encoded in the genomes of polyomaviruses, which are small double-stranded DNA viruses. STag is expressed early in the infectious cycle and is usually not essential for viral proliferation, though in most polyomaviruses it does improve replication efficiency. The STag protein is expressed from a gene that overlaps the large tumor antigen (LTag) such that the two proteins share an N-terminal DnaJ-like domain but have distinct C-terminal regions. STag is known to interact with host cell proteins, most notably protein phosphatase 2A (PP2A), and may activate the expression of cellular proteins associated with the cell cycle transition to S phase. In some polyomaviruses - such as the well-studied SV40, which natively infects monkeys - STag is unable to induce neoplastic transformation in the host cell on its own, but its presence may increase the transforming efficiency of LTag. In other polyomaviruses, such as Merkel cell polyomavirus, which causes Merkel cell carcinoma in humans, STag appears to be important for replication and to be an oncoprotein in its own right.

Minor capsid protein VP2 and minor capsid protein VP3 are viral proteins that are components of the polyomavirus capsid. Polyomavirus capsids are composed of three proteins; the major component is major capsid protein VP1, which self-assembles into pentamers that in turn self-assemble into enclosed icosahedral structures. The minor components are VP2 and VP3, which bind in the interior of the capsid.

References

  1. ↑ Tagliapietra A, Rotondo JC, Bononi I, Mazzoni E, Magagnoli F, Maritati M, Contini C, Vesce F, Tognon M, Martini F (2019). "Footprints of BK and JC polyomaviruses in specimens from females affected by spontaneous abortion". Hum Reprod. 34 (3): 433–440. doi:10.1093/humrep/dey375. hdl: 11392/2397214 . PMID   30590693. S2CID   58621197.
  2. ↑ Pahari A, Rees L (August 2003). "BK virus-associated renal problems-clinical implications" . Pediatr Nephrol. 18 (8): 743–748. doi:10.1007/s00467-003-1184-3. PMID   12802640.
  3. ↑ Tagliapietra A, Rotondo JC, Bononi I, Mazzoni E, Magagnoli F, Maritati M (2019). "Footprints of BK and JC polyomaviruses in specimens from females affected by spontaneous abortion". Hum Reprod. 34 (3): 433–440. doi:10.1093/humrep/dey375. hdl: 11392/2397214 . PMID   30590693. S2CID   58621197.
  4. ↑ Tagliapietra A, Rotondo JC, Bononi I, Mazzoni E, Magagnoli F, Maritati M (2019). "Footprints of BK and JC polyomaviruses in specimens from females affected by spontaneous abortion". Hum Reprod. 34 (3): 433–440. doi:10.1002/jcp.27490. hdl: 11392/2397717 . PMID   30590693. S2CID   53106591.
  5. ↑ Gupta G, Shapiro R, Thai N, Randhawa PS, Vats A (August 2006). "Low incidence of BK virus nephropathy after simultaneous kidney pancreas transplantation". Transplantation. 82 (3): 382–8. doi: 10.1097/01.tp.0000228899.05501.a7 . PMID   16906037. S2CID   12310204.
  6. ↑ Egli A; Infanti L; Dumoulin A; et al. (2009). "Prevalence of polyomavirus BK and JC infection and replication in 400 healthy blood donors". J Infect Dis. 199 (6): 837–46. doi: 10.1086/597126 . PMID   19434930.
  7. ↑ Fishman, J. A. (2002). "BK Virus Nephropathy – Polyomavirus Adding Insult to Injury". New England Journal of Medicine. 347 (7): 527–530. doi:10.1056/NEJMe020076. PMID   12181409.
  8. ↑ Elfadawy, NS; Flechner, SM; Xiaobo, L; Schold, J; Tian, D; Srinivas, TR; Poggio, E; Fatica, R; Avery, R; Mosaad, SB (2013). "The impact of surveillance and rapid reduction in immunosuppression to control BK virus-related graft injury in kidney transplantation". Transplant International. 26 (8): 822–32. doi: 10.1111/tri.12134 . PMID   23763289.
  9. ↑ Bista, BR; Ishwad, C; Wadowsky, RM; Manna, P; Randhawa, PS; Gupta, G; Adhikari, M; Tyagi, R; Gasper, G (2007). "Development of a Loop-Mediated Isothermal Amplification Assay for Rapid Detection of BK Virus". Journal of Clinical Microbiology. 45 (5): 1581–7. doi:10.1128/JCM.01024-06. PMC   1865893 . PMID   17314224.
  10. ↑ Gardner SD, Field AM, Coleman DV, Hulme B (June 1971). "New human papovavirus (B.K.) isolated from urine after renal transplantation". Lancet. 1 (7712): 1253–7. doi:10.1016/s0140-6736(71)91776-4. PMID   4104714.
  11. ↑ Hurdiss, Daniel L.; Morgan, Ethan L.; Thompson, Rebecca F.; Prescott, Emma L.; Panou, Margarita M.; Macdonald, Andrew; Ranson, Neil A. (April 2016). "New Structural Insights into the Genome and Minor Capsid Proteins of BK Polyomavirus using Cryo-Electron Microscopy". Structure. 24 (4): 528–536. doi:10.1016/j.str.2016.02.008. PMC   4826271 . PMID   26996963.
  12. 1 2 3 4 5 6 Ambalathingal, George R.; Francis, Ross S.; Smyth, Mark J.; Smith, Corey; Khanna, Rajiv (April 2017). "BK Polyomavirus: Clinical Aspects, Immune Regulation, and Emerging Therapies". Clinical Microbiology Reviews. 30 (2): 503–528. doi:10.1128/CMR.00074-16. ISSN   0893-8512. PMC   5355639 . PMID   28298471.
  13. 1 2 Martí-Carreras, Joan; Mineeva-Sangwo, Olga; Topalis, Dimitrios; Snoeck, Robert; Andrei, Graciela; Maes, Piet (31 July 2020). "BKTyper: Free Online Tool for Polyoma BK Virus VP1 and NCCR Typing". Viruses. 12 (8): 837. doi: 10.3390/v12080837 . ISSN   1999-4915. PMC   7472310 . PMID   32751885.
  14. 1 2 3 Giannecchini, Simone (27 May 2020). "Evidence of the Mechanism by Which Polyomaviruses Exploit the Extracellular Vesicle Delivery System during Infection". Viruses. 12 (6): 585. doi: 10.3390/v12060585 . ISSN   1999-4915. PMC   7354590 . PMID   32471033.
  15. 1 2 Zhou, Xianfeng; Zhu, Chunlong; Li, Hui (13 September 2023). "BK polyomavirus: latency, reactivation, diseases and tumorigenesis". Frontiers in Cellular and Infection Microbiology. 13. doi: 10.3389/fcimb.2023.1263983 . ISSN   2235-2988. PMC   10525381 . PMID   37771695.
  16. ↑ Yogo, Yoshiaki; Sugimoto, Chie; Zhong, Shan; Homma, Yukio (July 2009). "Evolution of the BK polyomavirus: epidemiological, anthropological and clinical implications". Reviews in Medical Virology. 19 (4): 185–199. doi:10.1002/rmv.613. ISSN   1052-9276. PMID   19530118.
  17. ↑ An, Ping; Sáenz Robles, Maria Teresa; Duray, Alexis M.; Cantalupo, Paul G.; Pipas, James M. (8 January 2019). Imperiale, Michael J. (ed.). "Human polyomavirus BKV infection of endothelial cells results in interferon pathway induction and persistence". PLOS Pathogens. 15 (1): e1007505. doi: 10.1371/journal.ppat.1007505 . ISSN   1553-7374. PMC   6338385 . PMID   30620752.
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