Human BK and JC polyomaviruses: Molecular insights and prevalence in Asia

Journal Pre-proof Human BK and JC Polyomavirus: Molecular insights and prevalence in Asia Iqra Hussain, Fareeda Tasneem, Usman Shah Gilani, Muhammad Imran Arshad, Muhammad Farhan ul Haque, Zaigham Abbas, Muhammed Umer, Naveed Shahzad

PII:

S0168-1702(19)30711-7

DOI:

https://doi.org/10.1016/j.virusres.2020.197860

Reference:

VIRUS 197860

To appear in:

Virus Research

Received Date:

4 October 2019

Revised Date:

31 December 2019

Accepted Date:

2 January 2020

Please cite this article as: Hussain I, Tasneem F, Shah Gilani U, Arshad MI, Farhan ul Haque M, Abbas Z, Umer M, Shahzad N, Human BK and JC Polyomavirus: Molecular insights and prevalence in Asia, Virus Research (2020), doi: https://doi.org/10.1016/j.virusres.2020.197860

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Human BK and JC Polyomavirus: Molecular insights and prevalence in Asia Iqra Hussain1, Fareeda Tasneem2, Usman Shah Gilani1, Muhammad Imran Arshad3, Muhammad Farhan ul Haque1, Zaigham Abbas4, Muhammed Umer5 and Naveed Shahzad1*.

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1. School of Biological Sciences, University of the Punjab, Lahore, Pakistan. 2. Department of Zoology, University of the Punjab, Lahore, Pakistan. 3. Institute of Microbiology, University of Agriculture Faisalabad, Pakistan. 4. Department of Microbiology and Molecular Genetics, University of the Punjab, Lahore, Pakistan. 5. Queensland Micro- and Nanotechnology Centre (QMNC), Griffith University, Nathan, QLD 4111, Australia.

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*Corresponding Author:

Highlights

The BKPyV and JCPyV establish asymptomatic and latent infection in human which is activated

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Naveed Shahzad Assistant Professor, School of Biological Sciences, University of the Punjab Lahore, Pakistan. Cell: 0092-3217840245 E-mail: [email protected]

as a consequence of immunosuppression. 

BKPyV and JCPyV have been linked with multiple human malignancies including BK Virus



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Associated Nephropathy and Progressive Multifocal Leukoencephalopathy, respectively. Overall, 4 subtypes of BKPyV and 14 subtypes of JCPyV, are widely distributed across the globe with the frequency of 80-90% in different populations. Previously published studies unanimously report high occurrence of both, BKPyV and JCPyV, in Asian populations with highest occurrence of BKPyV (66.7%) in Korea and JCPyV (88%) in Taiwan.

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ABSTRACT Polyomaviridae family consists of small circular dsDNA viruses. Out of the 14 human polyomaviruses described so far, BKPyV and JCPyV have been studied extensively since their discovery in 1971. Reportedly, both BKPyV and JCPyV are widely distributed across the globe with the frequency of 80-90% in different populations. The primary infection of these viruses is usually asymptomatic and latent which is activated as a consequence of immunosuppression. Activated BKPyV and JCPyV viruses lead to the development of BK Virus Associated

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Nephropathy and Progressive Multifocal Leukoencephalopathy, respectively. Immense progress has been made during the last few decades regarding the molecular understanding of

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polyomaviruses. Epidemiology of polyomaviruses has also been studied extensively. However, most of the epidemiological studies have focused on European and American populations.

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Therefore, limited data is available regarding the geographical distribution of these potentially oncogenic viruses in Asian countries. In this article, we have presented a compendium of latest

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advances in the molecular understanding of polyomaviruses and their pathobiology. We also present a comprehensive review of published literature regarding the epidemiology and prevalence of BKPyV and JCPyV in Asian regions. For this purpose, a thorough search of

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available online resources was performed. As a result, we retrieved 24 studies for BKPyV and 22 studies for JCPyV, that describe their prevalence in Asia. These studies unanimously report high

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occurrence of both BKPyV and JCPyV in Asian populations. The available data from these studies was categorized into two groups: on the basis of prevalence (low, medium and high) and disease development (healthy and diseased). Altogether, Korean population hasbeen evidenced to possess highest frequency of BKPyV (66.7%), while JCPyV was found to be most prevalent in Taiwan (88%). Due to high and ubiquitous distribution of these viruses, frequent studies are

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required to develop a better understanding regarding the epidemiology and pathobiology of these viruses in Asia.

Key Words: BK polyomavirus, JC polyomavirus, BKVAN, PML and Prevalence.

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1. Introduction Members of Polyomaviridae, a family of ubiquitous, host-specific viruses containing small circular dsDNA genome, naturally infect birds and mammals, including humans (DeCaprio & Garcea, 2013). So far, 14 different species of human polyomaviruses (HPyV) have been identified, of which BK polyomaviruses (BKPyV) and JC polyomavirus (JCPyV) were the first human polyomaviruses to be described. In fact, BKPyV and JCPyV were the only known human polyomaviruses for almost 40 years. BKPyV and JCPyV are similar to each other with nearly

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72% homology in their entire nucleotide sequences (Prado et al., 2018). However, non-coding control regions (NCCR) and capsid genes of BKPyV and JCPyV are most extensively mutated

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and rearranged to give rise to different genotypes. The BKPyV and JCPyV are categorized into 4 and 14 subtypes, respectively, that exhibit a wide and variable distribution among different

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regions of the world (Chehadeh et al., 2013). Both of these viruses primarily infect healthy individuals during their early ages and persist for life by establishing latency in different host cells/organism of the body that mainly include mononuclear blood cells and cells of the proximal

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renal tubules (Delbue et al., 2017). During latency, BKPyV and JCPyV do not cause any apparent damages to the host, therefore not manifesting any clinical symptoms (Bennett et al.,

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2012). However, under conditions of immunosuppression, reactivation of these viruses may occur, leading to a range of devastating complications. Such as, hemorrhagic cystitis and nephropathy

caused

by

BKPyV,

while

JCPyV

causing

progressive

multifocal

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leukoencephalopathy (PML) (Ahsan & Shah, 2006). Much work has been done to unravel the molecular machinery of Polyomaviridae family. New molecular insights into the genomic organization as well as variations have emerged in recent years. Similarly, structural and functional variations in various viral proteins as well as

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pathobiological and tissue tropism implications of these so-called variations have been a subject of extensive research. This increased understanding has led to better elucidation of mechanisms underlying various diseases caused by BKPyV and JCPyV species. Distribution of both virus species has also been extensively investigated during the past few decades, particularly in developed world where it has been found that 80-90% of the general human population is persistently infected with either BKPyV or JCPyV (Dalianis & Garcea, 2009). However, limited data is available from Asia. Therefore, pattern and extent of BKPyV and JCPyV distribution in 3

most of the Asian countries is not clear. Here we present a brief summary of latest advances in BKPyV and JCPyV research with a special emphasis on our understanding of mechanisms underlying various virus caused diseases. A comprehensive review of the available data regarding the distribution of BKPyV and JCPyV in Asia has also been carried out. Taking this task into consideration, scientific literature has been surveyed for data relating to the prevalence of BKPyV and JCPyV in Asia. Data for these viruses was categorized into healthy and diseased groups with relevant information like sample type, method of detection and place of data

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collection. This study will serve as a valuable resource for researchers and health professionals having the objective to perform epidemiological and viral characteristic studies. The analysis of the already available literature will also help in evaluating frequency of these polyomavirus

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infections, thus enabling better diagnosis and treatment approaches as well as preventive

2. The genomic organization of BKPyV and JCPyV

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measures.

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The genome size and organization of BKPyV and JCPyV viruses is similar to most of other human polyomaviruses except for a few differences. The genome of both, BKPyV and JCPyV, is divided into three functional regions: an early gene region, a late gene region and a non-coding

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control region (NCCR) (Ahsan & Shah, 2006; Prado et al., 2018) as depicted in Figure 1A and 1B.

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Unlike other polyomaviruses, the early region of BKPyV is transcribed into three tumor antigens: Large T antigen (LT), Small T antigen (ST), and an additional truncated T antigen (Trunc Tag) that plays a vital role in BKPyV mediated cellular transformation (Abend et al., 2009). The late region of BKPyV is translated into VP1, VP2, VP3, and an additional agnoprotein (Kamen et al., 1980). A wild type (archetypal) NCCR of BKPyV is arranged into

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five sequence blocks; O (142bp), P (68bp), Q (39bp), R (63bp) and S (63bp). The O block lies in the early proximal region that contains an origin of replication while the remaining four blocks are within late proximal region that undergoes high degree of rearrangements to give rise to different BKPyV strains (Gosert et al., 2008). In contrast, the genome of JCPyV bears a few differences in organization at some regions from BKPyV and other human polyomaviruses. For instance, the early region of JCPyV genome is transcribed into five T antigens; the LT, ST and three additional antigens known as T′135, T′136 and T′165 antigens. The latter three antigens are named on the basis of amino acid numbers that 4

interact with tumor suppressor protein pRB for their involvement in malignant transformation (Bollag et al., 2006). The JCPyV late region encodes four proteins; VP1, VP2, VP3 and agnoprotein similar to the case with BKPyV. The NCCR of wild type JCPyV is organized into seven regions that are A (36bp), B (23bp), C (55bp), D (66bp), E (18bp), F (69bp) and Ori (117bp). Notably, prototypical strains of JCPyV undergo multiple rearrangements in these NCCR units except Ori block that is usually conserved among all JCPyV subtypes (Assetta et al 2017).

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3. Structure and function of BKPyV and JCPyV proteins

The proteins encoded by BKPyV and JCPyV show significant homology albeit a few differences

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at certain regions (Diotti et al., 2013; Imperiale & Major., 2007). The LT of both these polyomaviruses essentially contains three motifs; a nuclear localization signal, DNA binding

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domain, and a helicase domainpossessingmultiple intrinsic biochemical activities thatregulate viral DNA replication and play role in cellular transformation. It also stimulates transcription of

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both early and late regions by interacting with NCCR through its DNA binding domains. Furthermore, LT of both viruses recruits several host proteins such as DNA polymerase-α at its J domain or DnaJ motif for replication of viral genome (Prado et al., 2018). It also contains a pRB

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protein binding motif LXCXE which promotes cell cycle progression by causing a loss of antiproliferative activity of the protein (Ambalathingal et al., 2017).

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The ST of both BKPyV and JCPyV contain an N-terminal region with two conserved zinc finger motifs that are involved in interactions with host protein phosphatase 2A (PP2A). The ST interacts with regulatory and catalytic subunit of PP2A that shifts substrate binding subunit in an orientation to which substrate fails to bind, therefore inhibiting phosphatase activity in host cell leading to cellular transformation (Baez et al., 2017). Detailed structure of LT and ST are shown

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in Figure 2.

Other T antigens such as Trunc Tag in BKPyV, and T′135, T′136 and T′165 in JCPyV, share amino acids with N terminal region of LT containing J domain, the pRB binding domain and the nuclear localization signal. These proteins localize in the nucleus and interact with pRB proteins via the LXCXE motif suggesting their probable roles in cellular transformation and viral DNA replication (Bollag et al., 2006&Baez et al.,2017). Late region of both BKPyV and JCPyV is transcribed into two mRNAs; 16S and 19S.The 16S mRNA is translated into viral capsid protein (VP1), while 19S generates VP2, VP3 and 5

agnoprotein but an additional VP4 in BKPyV (Henriksen et al., 2016). Late gene region is transcribed from the strand complementary to the one used for early region (Ambalathingal et al., 2017). TheVP1 is a dominant structural protein with almost 75% of polyomavirus capsid made of VP1. It contains domains that interact with cellular receptors, which in turn facilitate its binding with host plasma membrane and penetration into the cells. VP1 protein bears epitopes that enhance pathogenicity of the virus and is capable of generating virus like particles without the need for participation of other viral proteins. Role of VP2 and VP3 is not well known,

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however, it has been suggested that these proteins are involved in the maintenance of capsid structure. The VP4 in BKPyV is essential for infectivity of virus but its mechanism is yet unknown (Henriksen et al., 2016; Prado et al., 2018). Agnoprotein is translated from late region

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mRNA and itself is not a part of the virion.. Agnoprotein of BKPyV is reported to be involved in exocytosis and virion release (Johannessen et al., 2011; Panou et al., 2018). It is also known to

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interact with several cellular partners and inhibits DNA replication (Gertis et al., 2015)Studies on JCPyV suggest that phosphorylation plays a vital role in determining the function of its

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agnoprotein as its phosphorylated form is found in cytoplasm while the dephosphorylated is translocated to nucleus (Ambalathingal et al., 2017). Agnoprotein of JCPyV plays a crucial role

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in transcription, replication and nuclear or cellular release of the virus. It is also known to dysregulates cell cycle progression (Darbinyan et al., 2002) and inhibits DNA repair (Darbinyan

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et al., 2004). (A comparison between proteins of both viruses is shown in Table 1. 4. Subtypes of BKPyV and JCPyV

Classification of BKPyV and JCPyV species is based on variation in VP1 capsid protein sequence. Approximately 95% of VP1 amino acid sequence is homologous among all genotypes while the remaining 5% contributes to the antigenic variability. On this basis, BKPyV is

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classified into four (I-IV) subtypes. The subtype I is distributed worldwide and is further subdivided into four subgroups; Ia, Ib1, Ib2 and Ic. Subtypes II and III are very rare while genotype IV distribution is reported in northeastern Asia and Europe (Ikegaya et al., 2006). Hariharan et al. reported that BKPyV prototype strain Dunlop (Dun),MM and GS strains belong to subtype I, SB strain to group II, AS strain to group III and MG strains to group IV. It is important to mention that no correlation between infecting genotype and specific clinical characteristics has so far been reported (Hariharan, 2006; Wunderink et al.,2019).

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JCPyV is classified into 14 subtypes/genotypes sharing minor genomic differences in VP1, LT antigen and NCCR sequence and exhibiting distinct geographic distribution. Subtype 1, 4 and 5 are more prevalent in European population, subtype 2A in Japanese, 2B and 2C in Eurasian, 2D in Indian, while 2E is most commonly found in Australian. Subtype 3 is found in South Africa and subtype 6 in central Africa. Subtype 7A, 7B and 7C are isolated from Chinese and Asian populations and subtype 8 is present in Pacific Island (Pavesi, 2005; Hu et al.,2018). Table 2

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briefly describes the geographical distribution of BKPyV and JCPyV subtypes.

5. Cell and tissue tropism of BKPyV and JCPyV

The urinary tract is considered as primary predilection site for both BKPyV and JCPyV.

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Cytological and molecular analysis of biopsy samples from urinary tract of infected individuals and immunocompromised patients have shown foci of these viruses confirming that epithelial

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cells of kidney, renal tubules, ureters, bladder and urethra are the site of productive viral infection (Boldorini et al., 2005; Singh et al., 2006). The antigens of BKPyV can also be

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detected in many other tissues and cell types such as; respiratory tract, skin, bone, brain, colon and blood (Abend et al., 2009). BKPyV has also been detected in oral fluids which indicates its

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potential oral transmission route (Burger-Calderon et al.,2014). Contrary to BKPyV, JCPyV has a restricted tissue tropism as it requires specific receptors to successfully enter and infect the cells. Recognition and interaction of JCPyV with host α 2, 6-Linked Sialic Acid Binding receptor

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is key for virus internalization and infection (Dugan et al., 2008). Oligodendrocytes and astrocytes of brain, kidney cells, lung epithelial cells and B lymphocytes express this receptor, and are considered as primary sites of JCPyV infection and reactivation (Eash et al., 2004). The primary target cells and site of reactivation for BKPyV and JCPyV are collectively described in

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Figure 3.

6. Life cycle of BKPyV and JCPyV Human polyomaviruses display carbohydrate binding protein VP1 on their surface that acts as ligand molecule for specific receptors present on different host cells. Binding of polyomavirus capsid to the cellular receptors internalizes the virus either by calveolae or clathrin mediated endocytosis pathways. The BKPyV binds with gangliosides GD1b and GT1b (glycan receptors) and enters in the cell by calveolae dependent pathway (Low et al., 2006). On the other hand, JCPyV interacts with sialylated oligosaccharides and the serotonin 5-hydroxytryptamine 7

superfamily 2 receptor 5-HT (2A) and enters via clathrin mediated endocytosis (Neu et al., 2010., Mayberry et al., 2019). A comparative schematic of BKPyV and JCPyV life cycles is shown in Figure4. Briefly, clathrin/calveolae vesicles are transported through endoplasmic reticulum where capsid is partially removed and genome enters in the nucleus via nuclear pores (Dugan et al., 2006). Immediately after entry into the nucleus, the early genes of both BKPyV and JCPyV are transcribed to produce viral tumor antigens (LT and ST). The LT antigen binds to the origin of replication in NCCR to initiate viral genome replication by bidirectional replication

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mechanism. It also initiates expression of late genes and down regulates transcription of early genes. The mRNA of late genes undergoes translation in cytoplasm and expresses viral capsid proteins and agnoprotein. Later on, viral capsid proteins are transported to the nucleoplasm

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where these are assembled into a capsid structure along with the viral mini chromosome. Polyomaviral mini chromosome is made up of viral genome wrapped around host cell histones.

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The mature virions of BKPyV and JCPyV are released from the host cell either by exocytosis or

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cell death (Daniels et al., 2007; Bhattacharjee & Chattaraj, 2017).

7. Transmission dynamics of BKPyV and JCPyV

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Decades after the discovery of BKPyV and JCPyV, no definite route of transmission has been determined for these viruses among human population. For BKPyV, respiratory route is considered as a primary route of transmission (Boldorini et al., 2010). However, the transmission

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of BKPyV has also been reported via other routes including trans-placental, oral, fecal and blood transfusion (Ambalathingal et al., 2017, Burger-Calderon et al., 2014). The BKPyV can reactivate in states of cellular immunodeficiency. Major sites of BKPyV infection and reactivation are kidney, eyes, liver, lungs and brain. To date, kidney is the most reported site of BKPyV infection and reactivation. BKPyV also infects lungs and brain, although at much lower

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rates, where its infection is manifested as pneumonitis and meningoencephalitis, respectively. Immunocompromised individuals, pregnant women, diabetics and the elderly appear to be at higher risk of these diseases (Reploeg et al., 2001). For JCPyV, contaminated water, food and fomites are considered as main sources of transmission (Bofill-Mas et al., 2003).The main sites of JCPyV infection are tonsils, kidney and gastrointestinal tract. Virus remains persistent in the GIT and tubular epithelial cells of the kidneys, where it continues to replicate and shed virus particles in the urine. JCPyV infected cells are capable of crossing blood-brain barrier and enter 8

into the central nervous system, where it infects oligodendrocytes and astrocytes (Chapagain & Nerurkar., 2010). Individuals with immune deficiency, chronic immunosuppressive medications and autoimmune diseases are at the risk of JCPyV infection (Theodoropoulos et al., 2005., Bhattacharjee & Chattaraj, 2017). 8. Pathophysiology of BKPyV and JCPyV Polyomaviruses can cause pathogenic effects and clinical illness only in immunocompromised individuals. Risk factors associated with reactivation are more prevalent in individuals of elder

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age with meager immunity, transplantation and immunosuppressant therapies (Wong et al.,

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2007). 8.1 BKPyV

BKPyV associated nephropathy (BKVAN) and hemorrhagic cystitis (HC) are the most common

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clinical conditions caused by BKPyV infection. Other less commonly associated illnesses include liver diseases like hepatitis, pneumonitis and some cancer types including lung

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carcinoma, Kaposi’s sarcoma, brain, liver, pancreas and urinary tract carcinomas (Tan &

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Koralnik, 2009). Briefly, BKPyV associated diseases are discussed below: 8.1.1 BKPyV associated nephropathy

BKVAN is a condition in which transplant is rejected in renal transplant recipients and is

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characterized by BKPyV replication in renal epithelial cells, renal dysfunction and sometimes complete loss of kidney. It is observed that 30-50% of kidney transplant individuals develop BKVAN within few months of grafting. BKVAN is detected by presence of hematuria and high levels of serum creatinine (Bressollette-Bodin et al., 2005; Vasudev et al., 2005). 8.1.2 Hemorrhagic cystitis

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Hemorrhagic cystitis (HC) is characterized by urinary bladder hemorrhage, urinary retention and renal failure. Symptoms of HC include sudden onset of hematuria, dysuria and suprapubic pain. It usually develops in patients that have undergone allogeneic hematopoietic stem cell transplantation (HSCT). Approximately 50% of HSCT recipients develop BKPyV reactivation that results in hemorrhagic cystitis (Silva et al., 2010). 8.1.3 Pulmonary and hepatic diseases 9

BKPyV reactivation in immunocompromised individuals may also lead to the development of pulmonary fibrosis, characterized by scars on lung, shortening of breath and interstitial pneumonia. Liver dysfunction has also been reported as a possible consequence of BKPyV infection. BKPyV reactivation is associated with transient increase in liver enzymes and BKPyV shedding in urine (Ambalathingal et al., 2017). 8.1.4 BKPyV and cancer Oncogenic potential of polyomaviruses is generally due to the activity of T antigens that have an

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inhibitory action on host tumor suppressor proteins (Rinaldo et al., 2013). BKPyV reactivation is not directly linked to any specific carcinoma but its DNA can be detected in many tumors

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including rhabdomyosarcoma, lung carcinoma, Kaposi’s sarcoma, brain, liver, pancreas and urinary tract carcinomas. The BKPyV DNA prevalence has been reported to be 46% in brain

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tumors, 20% in Kaposi’s sarcoma and 60% in urinary tract tumors (Fraase et al., 2011; Ambalathingal et al., 2017). Association of BKPyV with urinary tract carcinomas can possibly

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be attributed to the fact that urinary tract is major site of BKPyV latency (Fraase et al., 2011). BKPyV DNA is also found in epithelial cells of Proliferative Inflammatory Atrophy (PIA) ducts of prostate tumor specimens (Das et al., 2004). BKPyV may contribute to change in normal

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tissue morphology and prostate cancer development by Tag-mediated p53 interactions (Tognon & Provenzano, 2015). Despite the detection of BKPyV genome in different carcinomas, there is

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no certain evidence that BKPyV is causative agent of any type of human cancer or it works as a cofactor in pathogenesis of any cancer (Ambalathingal et al., 2017). 8.2 JCPyV

Activation of JCPyV is mainly associated with Progressive Multifocal Leukoencephalopathy (PML). However, it has also been found to be associated with the pathogenesis of some cancer

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types as described in the following passages. 8.2.1 Progressive multifocal leukoencephalopathy Progressive Multifocal Leukoencephalopathy (PML) is a disease in which central nervous system is demyelinated because of JCPyV cytopathic effects. The JC polyomavirus replicates in permissive myelin producing cells oligodendrocytes and astrocytes in immunocompromised patients. PML is characterized by limb paresis, seizures, abnormal coordination and visual 10

disturbances (Lima et al., 2006). Increased incidence of PML in autoimmune diseases and AIDS has been reported. Approximately 5% of HIV infected patients have PML due to coinfection of JC virus. However, it is not clear whether JCPyV remains latent in CNS and reactivates upon immunosuppression or it persists in lymphocytes from where it can transport to CNS after reactivation (Berger et al., 2009; Bloomgren et al., 2012). 8.2.2 JCPyV and cancer JCPyV DNA has been detected in 20-30% of colorectal carcinoma patients and it is hypothesized

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that JCPyV is specifically linked with this cancer type (Coelho et al., 2010). It has been observed that 96% of colorectal cancer tissues contain JCPyV DNA sequences. As colorectal epithelial

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cells are non-permissive to JCPyV, its infection is not detected in early stages which gradually leads to tumor (Bhattacharjee & Chattaraj, 2017). JCPyV associated colorectal carcinomas are

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more prevalent in immunocompromised individuals that have undergone liver or kidney transplantation (Haagsma et al., 2001). JCPyV DNA is also detected in 58.3% prostate cancer

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cases (Anzivino et al., 2015). Likewise, JCPyV is also detected in glioma like medulloblastomas, oligodendrogliomas, astrocytomas, ependymomas, glioblastoma as well as gastrointestinal and anal cancers, however limited data is available regarding the role and occurrence of JCPyV

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infection in these cancers (Burnett-Hartman et al., 2008). In a study, 57% to 83% of brain tumor tissues with or without PML were found to be positive for JCPyV DNA as well as expression of

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T antigens. JCPyV does not bear causative role in any type of human cancer but it can be implicated from different studies that it may act as a cofactor in tumor formations (Bhattacharjee & Chattaraj, 2017).

9. Epidemiology of BKPyV and JCPyV

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9.0.1 BKPyV

BKPyV infection is ubiquitous. It is present in all parts of the world, in both developed and developing countries. However, the majority of studies pertaining to BKPyV epidemiology have been performed in European population where its seropositivity rates range was between 55% and 85% (Rollison et al., 2006; Antonsson et al., 2010). Furthermore, seropositivity of BKPyV was reported 98 % in a large study on Dutch blood donors (Kamminga et al., 2018). Similar to Europe, high BKPyV seropositivity (up to 82%) was also reported in USA (Kean et al., 2009). It 11

has been reported that the highest seroprevalence occurs in early childhood (Egli et al., 2009). In fact, primary BKPyV infection mostly occurs in early ages, however, it may remain asymptomatic and latent for several years. Seroprevalence of BKPyV generally ranges between 60 to 90% in adulthood and up to 99% in the middle ages. However, after 40-50 years of age, seroprevalence of BKPyV starts to decline (Rollison et al., 2006; Antonsson et al., 2010). Molecular detection of BKPyV is mostly carried out by using PCR based techniques that report BKPyV prevalence from 4% to 27% in different age groups (Di Taranto et al., 1997).

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9.0.2 JCPyV

Similar to BKPyV, JCPyV is also globally distributed, infecting 70% to 90% of human

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population across the world. Most people acquire JCPyV in childhood or adolescence (Shackelton et al., 2006). A European study has indicated that anti-JCPyV seroprevalence is 58%

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in 20-29 years’ age group which increases to 68% among 50-59 years’ age group (Kamminga et al., 2018). Similar frequencies were monitored in Australian population where anti-JCPyV

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seropositivity was 60% in people of less than 50 years of age, 68% in 50-60 years’ age group, and 64% in population older than 70 years (Sadeghi et al., 2015). In USA, JCPyV seroprevalence has been reported up to 39% in healthy adults (Kean et al., 2009). As far as the

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healthy individuals are concerned, the JCPyV DNA is reported to shed with variable frequencies in blood and urine in different populations (Pires et al., 2011; Nali et al., 2012).

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9.1 Prevalence in Asia 9.1.1 BKPyV

An extensive search from available online databases including NCBI and PubMed was made for BKPyV prevalence in Asia. Different key words and terms e.g. BKPyV, BKPyV in Asia, were used in order to retrieve relevant publications. Only 19studies from 13 Asian countries have been

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found on this topic. Among them, most of the studies were performed on renal transplant recipients, as reactivation of this virus is associated with immunosuppression. Overall, molecular prevalence of BKPyV was found to be comparatively higher in Asian region than Europe. Notably, the prevalence of BKPyV in renal transplantation and immunosuppressive therapy patients is higher as compared to the healthy population. Table 3 summarizes the findings of all available studies describing frequencies of BKPyV detection in healthy as well as in various disease conditions, in different Asian countries. Briefly, the circulation of BKPyV was significantly higher in persons with either renal transplant or HIV infection in comparison to the 12

healthy individuals. Overall (in both healthy and disease groups), BKPyV viremia and viruria ranged between 2% and 67%. Among healthy population, the lowest BKPyV frequency was reported from Kuwait (3%) while the highest frequency was found in Pakistan (27.1%) (Chehadeh et al., 2013, Hussain et al., 2017). On the other hand, in diseased group, frequency in renal transplant recipients was as high as 67% in Republic of Korea (Yoon et al., 2015). Based upon the available data, the Asian countries were categorized into low (≤10%), medium (1030%) and high (≥30%)groups in term of BKPyV prevalence and depicted on the map (Figure 5).

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9.1.2 JCPyV

Our literature searches from online databases (NCBI PubMed) using different key words such as

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JCPyV, JCPyV in Asia, found only 21 studies from 13 different Asian countries that reported prevalence of JCPyV among various population groups. A high prevalence of JCPyV has been

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reported in patients with multiple sclerosis and colorectal cancer. Data relating to JCPyV detection in healthy as well as different disease conditions from all of these studies is tabulated in

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Table 4. Briefly, the prevalence of JCPyV in Asian countries ranges from 1.6% to 90% among different patient cohorts while in healthy population prevalence from 3% in Kuwait to 38% in Iran has been observed (Chehadeh et al., 2013, Bozorgi et al., 2012). The countries of Asia with

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available JCPyV prevalence data are categorized into low (≤10%), medium (10-30%) and high (≥30%)in terms of JCPyV existence (Figure 6).

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10. Diagnosis of BKPyV and JCPyV infection

The early diagnosis of BKPyV and JCPyV reactivation is of foremost importance for the prevention of possible severe outcomes. The monitoring and diagnosis of these polyomaviruses’ infections can be performed through histological and cytological tests with the help of microscopy by detecting decoy cells in urine specimen. The serological methods that are based

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on antibodies’ detection like ELISA, RIA, and haemagglutination inhibition test are also widely used (Hamilton et al., 2000). Molecular diagnosis of BKPyV and JCPyV is usually based on the detection of viral genome present in the specimen. BKPyV DNA is generally detected in urine sample of both symptomatic and asymptomatic condition by PCR techniques because viruria is many folds higher than viremia (Randhaw et al., 2004). Neuroimaging is useful in diagnosis of JCPyV infection in PML cases, however brain biopsy is the most reliable diagnostic approach for PML with 64-96% sensitivity and 100% specificity (Tan & Koralnik, 2009). As it is difficult 13

to take brain tissues for biopsy, JCPyV can also be detected in cerebral spinal fluid through PCR techniques with variable specificities. Plasma JCPyV DNA detection cannot be used as a marker of PML but it can be a sign of PML infection in later ages (Alstadhaug, 2014). Diagnosis of BKPyV and JCPyV reactivation in diseases is categorized into three stages: possible, presumptive and proven diagnosis. 1. Possible diagnosis is based on real time PCR technique and the stage is defined by viral load greater than 107 copies in urine while very low in plasma.

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2. Presumptive diagnosis includes both PCR and cytological studies, viral load increases in both urine and plasma and decoy cells can also be detected in urine.

3. Proven diagnosis is based on histopathological findings in addition to viruria, viremia and

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decoy cells (Hirsch & Randhawa, 2013).

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11. Treatment of BKPyV and JCPyV infection

There is no specific antiviral drug available for polyomavirus infection, therefore, enhancing the

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host immunity is considered as major treatment option. However, some common antiviral drugs like cidofovir, quinolones and leflunomide are used in combination with immunity boosting drug for the treatment of BKPyV and JCPyV infection (Kadambi et al., 2003; Wu & Harris, 2008). In

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HIV infected PML patients a combinational antiretroviral therapy (cART) or highly active antiretroviral therapy (HAART) is most efficient that keeps HIV infection under control as well

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as reduces the chances of JCPyV reactivation (Haddow et al., 2010). Cytarabine is a chemotherapeutic drug that is reported to inhibit JCPyV replication in vitro (Marzocchetti et al., 2009). Mitrazapine being a serotonin receptor inhibitor also has a role in inhibition of JCPyV infection (Verma et al., 2007).

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12. Conclusion

The polyomaviruses BKPyV and JCPyV are highly prevalent in human populations but only cause clinical diseases among immunocompromised patients. Different subtypes are distributed among different regions of world. Our analysis shows that BKPyV positivity is high among renal transplant recipients, in both blood and urine samples (up to 67%).JCPyV is less frequently related to kidney transplantation but more often with cancers and autoimmune disorders. In healthy population JCPyV is present with 38% individuals while BKPyV positivity is 27%.

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Situation analysis, transmission dynamics and epidemiological evidence of BKPyV and JCPyV in Asian region will be helpful in devising control and preventive strategies for polyomaviruses

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associated disease of public health.

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REFERENCES

Jo

ur na

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Abend, J. R., Joseph, A. E., Das, D., Campbell-Cecen, D. B., Imperiale, M. J., 2009. A truncated T antigen expressed from an alternatively spliced BK virus early mRNA. Journal of General Virology. 90, 1238-1245. Agostini, H. T., Yanagihara, R., Davis, V., Ryschkewitsch, C. F., Stoner, G. L., 1997. Asian genotypes of JC virus in Native Americans and in a Pacific Island population: markers of viral evolution and human migration. Proceedings of the National Academy of Sciences United States of America. 94, 14542-14546. Ahsan, N., Shah, K. V., 2006. Polyomaviruses and human diseases. Advances in Experimental Medicine and Biology. 577, 1-18. Alroughanni, R., Akhtar, S., Ahmed, S., Al-Hashel, J., 2018. A longitudinal study of JC virus serostatus stability among multiple sclerosis patients. Multiple Sclerosis and Related Disorders. 20, 132-135. Al-Muaala, A. M., Al-Asaady, R. A., Al-Fatlawi, S. N., 2018. The Detection of BK Virus by Quantitative PCR of Plasma as Screening Test to Identify Renal Transplant Recipients at Risk of BK Virus Nephropathy. Al-Kufa University Journal of Biology. 10, 2311-6544. Alstadhaug, K. B., Croughs, T., Henriksen, S., 2014. Treatment of Progressive Multifocal Leukoencephalopathy with Interleukin 7. JAMA Neurology. 71, 1030-1035. Ambalathingal, G. R., Francis, R. S., Smyth, M. J., Smith, C., Khanna, R., 2017. BK Polyomavirus: Clinical Aspects, Immune Regulation, and Emerging Therapies. Clinical Microbiology Reviews. 30, 503-528. Antonsson, A., Green, A. C., Mallitt, K. A., 2010. Prevalence and stability of antibodies to the BK and JC polyomaviruses: a long-term longitudinal study of Australians. Journal of General Virolgy. 91, 1849-1853. Anzivino, E., Rodio, D. M., Mischitelli, M., Bellizzi, A., Sciarra, A., Salciccia, S., Pietropaolo, V., 2015. High Frequency of JCPyV DNA Detection in Prostate Cancer Tissues. Cancer Genomics and Proteomics. 12, 189-200. Aoyama, S., Mori, M., Uzawa, A., Uchida, T., Masuda, H., Ohtani, R., Kuwabara, S., 2018. Serum anti-JCPyV antibody indexes in Japanese patients with multiple sclerosis: elevations along with fingolimod treatment duration. Journal of Neurology. 265, 11451150. Arun-ngamwong, T., Sungkanuparph, S., 2010. JC Virus DNA Detection in Cerebrospinal Fluid of AIDS Patients with Progressive Multifocal Leukoencephalopathy. Journal of Infectious Diseases and Antimicrobial Agents. 27, 23-32. Baez, C. F., Brandão V. R., Villani, S., Delbue, S., 2017. Human Polyomaviruses: The Battle of Large and Small Tumor Antigens. Virology: Research and Treatment. 8, 1178122X17744785. Bennett, S. M., Broekema, N. M., Imperiale, M. J., 2012. BK polyomavirus: emerging pathogen. Microbes and Infection. 14, 672-683.

16

Jo

ur na

lP

re

-p

ro

of

Bhattacharjee, S., Chakraborty, T., 2004. High reactivation of BK virus variants in Asian Indians with renal disorders and during pregnancy. Virus Genes. 28, 157-168. Bloomgren, G., Richman, S., Hotermans, C., Subramanyam, M., Goelz, S., Natarajan, A., Lee, S., Plavina, T., Scanlon, J. V., Sandrock, A., Bozic, C., 2012. Risk of natalizumabassociated progressive multifocal leukoencephalopathy. The New England Journal of Medicine. 366, 1870-1880. Bofill-Mas, S., Girones, R.,2003. Role of the environment in the transmission of JC virus. Journal of Neurovirology. 9, 54-58. Bollag, B., Kilpatrick, L. H., Tyagarajan, S. K., Tevethia, M. J., Frisque, R. J., 2006. JC virus T'135, T'136 and T'165 proteins interact with cellular p107 and p130 in vivo and influence viral transformation potential. Journal of Neurovirology, 12, 428-442. Boldorini, R., Veggiani, C., Barco, D., Monga, G., 2005. Kidney and urinary tract polyomavirus infection and distribution: molecular biology investigation of 10 consecutive autopsies. Archives of Pathology and Lab Medicine. 129, 69-73. Boldorini, R., Allegrini, S., Miglio, U., Nestasio, I., Paganotti, A., Veggiani, C., Monga, G., Pietropaolo, V., 2010. BK virus sequences in specimens from aborted fetuses. Journal of Medical Virology. 82, 2127-2132. Boobes, Y., Bernieh, B., Hussain, Q., Al Omary, H., Al Hakim, M., Abayechi, F., Ahmed, M., 2015. Prevalence of polyomavirus among United Arab Emirates kidney transplant recipients: results from a single center. Transplantation Proceedings. 47, 1143-1145. Bozorgi, S. M., Tahaei, S. M. E., Mohebbi, S. R., Sahba, N., Damavand, B., Romani, S., Mohebbi, A., 2012. Molecular prevalence of JC virus in Tehran, Iran. Gastroenterology and Hepatology from Bed to Bench. 5, 84. Bressollette-Bodin, C., Coste-Burel, M., Hourmant, M., Sebille, V., Andre-Garnier, E., ImbertMarcille, B. M., 2005. A prospective longitudinal study of BK virus infection in 104 renal transplant recipients. American Journal of Transplantation. 5, 1926-1933. Brown, P., Tsai, T., Gajdusek, D. C., 1975. Seroepidemiology of Human Papovaviruses Discovery of Virgin Populations and some unusual patterns of Antibody Prevalence among remote peoples of the World. American Journal of Epidemiology. 102, 331-340. Burger-Calderon, R., Madden, V., Hallett, R. A., Gingerich, A. D., Nickeleit, V., WebsterCyriaque, J., 2014. Replication of oral BK virus in human salivary gland cells. Journal of virology. 88, 559–573. Burnett-Hartman, A. N., Newcomb, P. A., Potter, J. D., 2008. Infectious agents and colorectal cancer: A review of Helicobacter pylori, Streptococcus bovis, JC virus, and human papillomavirus. Cancer Epidemiology, Biomarkers & Prevention. 17, 2970-2979. Chattaraj, S., Bera, N., Dutta, C., Bhattacharjee, S., 2015. Quantification of human polyomavirus JC virus load in urine and blood samples of healthy tribal populations of North-Eastern part of West Bengal, India. Indian Journal of Medical Microbiology. 33, 491.

17

Jo

ur na

lP

re

-p

ro

of

Chapagain, M. L., Nerurkar, V. R., 2010. JCPyV infection of human B lymphocytes: A possible mechanism for JCPyV transmigration across the blood-brain barrier. The Journal of Infectious Diseases. 202, 184-191. Chehadeh, W., Kurien, S. S., Nampoory, M. R., 2013. Molecular characterization of BK and JC viruses circulating among potential kidney donors in Kuwait. BioMed Research International. 2013, 1-7. Chen, Q., Zheng, H. Y., Zhong, S., Ikegaya, H., He, H. X., Wei, W., He, Y. Y, Kobayashi, N., Kitamura, T. T., Yogo, Y., 2006. Subtype IV of the BK polyomavirus is prevalent in East Asia. Archives of virology. 151, 2419-2429. Coelho, T. R., Almeida, L., Lazo, P. A., 2010. JC virus in the pathogenesis of colorectal cancer, an etiological agent or another component in a multistep process?. Virology Journal. 7, 42. Cui, X., Wang, J. C., Deckhut, A., Joseph, B. C., Eberwein, P., Cubitt, C. L., Stoner, G. L., 2004. Chinese strains (Type 7) of JC virus are Afro-Asiatic in origin but are phylogenetically distinct from the Mongolian and Indian strains (Type 2D) and the Korean and Japanese strains (Type 2A). Journal of Molecular Evolution. 58, 568-583. Dalianis, T., Garcea, R. L., 2009. Welcome to the Polyomaviridae. Seminars in Cancer Biology. 19, 209-210. Daniels, R., Sadowicz, D., Hebert, D. N., 2007. A very late viral protein triggers the lytic release of SV40. PLoS Pathology. 3, e98. Darbinyan, A., Darbinian, N., Safak, M., Radhakrishnan, S., Giordano, A., Khalili, K., 2002. Evidence for dysregulation of cell cycle by human polyomavirus, JCV, late auxiliary protein. Oncogene. 21:5574-81. Darbinyan, A., Dorota, S., Nune, D., Shohreh, A., Martyn, K. W., Kamel, K., 2004. Role of JC Virus Agnoprotein in DNA RepairJ Virol. 78: 8593–8600. Das, D., Shah, R. B., Imperiale, M. J., 2004. Detection and expression of human BK virus sequences in neoplastic prostate tissues. Oncogene. 23, 7031-7046. DeCaprio, J. A., Garcea, R. L., 2013. A cornucopia of human polyomaviruses. Nature Reviews Microbiology. 11, 264-276. Delbue, S., Comar, M., Ferrante, P., 2017. Review on the role of the human Polyomavirus JC in the development of tumors. Infectious agents and Cancer, 12, 10. doi:10.1186/s13027-0170122-0 Diotti, R. A., Nakanishi, A., Clementi, N., Mancini, N., Criscuolo, E., Solforosi, L., Clementi, M., 2013. JC polyomavirus (JCV) and monoclonal antibodies: friends or potential foes?. Clinical & Developmental Immunology. 2013, 967581. Di Taranto, C., Pietropaolo, V., Orsi, G. B., Lin, L., Sinibaldi, L., Degener, A. M., 1997. Detection of BK polyomavirus genotypes in healthy and HIV-positive children. European Journal of Epidemiology. 13, 653-657. Dolei, A., Pietropaolo, V., Gomes, E., Di Taranto, C., Ziccheddu, M., Spanu, M. A., Degener, A. M., 2000. Polyomavirus persistence in lymphocytes: prevalence in lymphocytes from

18

Jo

ur na

lP

re

-p

ro

of

blood donors and healthy personnel of a blood transfusion centre. Journal of General Virology. 81, 1967-1973. Dörries, K., 1997. Molecular biology and pathogenesis of human polyomavirus infections. Developments in Biological Standardization. 94, 71-79. Dugan, A. S., Eash, S., Atwood, W. J., 2006. Update on BK virus entry and intracellular trafficking. Transplant Infectious Disease. 8, 62-67. Dugan, A. S., Gasparovic, M. L., and Atwood, W. J., 2008. Direct correlation between sialic acid binding and infection of cells by two human polyomaviruses (JC virus and BK virus). Journal of Virology. 82, 2560-2564. Eash, S., Tavares, R., Stopa, E. G., Robbins, S. H., Brossay, L., Atwood, W. J., 2004. Differential Distribution of the JC Virus Receptor-Type Sialic Acid in Normal Human Tissues. The American Journal of Pathology. 164, 419-428. Fraase, K., Hart, J., Wu, H., Pang, X., Ma, L., Grant, F., 2011. BK virus as a potential co-factor for HPV in the development of cervical neoplasia. Annals of Clinical and Laboratory Science. 42, 130-134. Funahashi, Y., Kato, M., Fujita, T., Tsuruta, K., Inoue, S., Gotoh, M., 2014. Correlation between Urine and Serum BK Virus Levels after Renal Transplantation. Transplantation proceedings. 46, 567-569. Gerits, N., Johannessen, M., Tümmler, C., Walquist, M., Kostenko, S., Snapkov, I., Loon, B. V., Ferrari, E., Hübscher, U., Moens, U., 2015. Agnoprotein of polyomavirus BK interacts with proliferating cell nuclear antigen and inhibits DNA replication. Virology Journal; 12: 7. Gosert, R., Rinaldo, C. H., Funk, G. A., Egli, A., Ramos, E., Drachenberg, C. B., Hirsch, H. H., 2008. Polyomavirus BK with rearranged noncoding control region emerge in vivo in renal transplant patients and increase viral replication and cytopathology. Journal of Experimental Medicine. 205, 841-852. Haagsma, E. B., Hagens, V. E., Schaapveld, M., van den Berg, A. P., de Vries, E. G., Klompmaker, I. J., Jansen, P. L., 2001. Increased cancer risk after liver transplantation: a population-based study. Journal of Hepatology. 34, 84-91. Haddow, L. J., Colebunders, R., Meintjes, G., Lawn, S. D., Elliott, J. H., Manabe, Y. C., Boulware, D. R., 2010. Cryptococcal immune reconstitution inflammatory syndrome in HIV-1-infected individuals: proposed clinical case definitions. The Lancet Infectious Diseases. 10, 791-802. Haghighi, M. F., Seyyedi, N., Farhadi, A., Zare, F., Kasraian, L., Dehbidi, G. R. R., Ranjbaran, R., Behzad-Behbahani, A., 2019. Polyomaviruses BK and JC DNA infection in peripheral blood cells from blood donors, The Brazilian Journal of Infectious Diseases. 23, 22-26. Hamilton, R. S., Gravell, M., Major, E. O., 2000. Comparison of antibody titers determined by hemagglutination inhibition and enzyme immunoassay for JC virus and BK virus. Journal of Clinical Microbiology. 38, 105-109.

19

Jo

ur na

lP

re

-p

ro

of

Hariharan, S., 2006. BK virus nephritis after renal transplantation. Kidney International. 69, 65562. Henriksen, S., Hansen, T., Bruun, J. A., Rinaldo, C. H., 2016. The Presumed Polyomavirus Viroporin VP4 of Simian Virus 40 or Human BK Polyomavirus Is Not Required for Viral Progeny Release. Journal of Virology. 90, 10398-10413. Hirsch, H. H., Randhawa, P., 2013. BK Polyomavirus in Solid Organ Transplantation. American Journal of Transplantation. 4, 179-188. Hsieh, M. C., Hung, C. W., Chiou, H. L., Yang, S. F., 2013. Effect of a BK viruria reaction detected by qualitative polymerase chain reaction on the renal function of kidney transplant recipients. Molecular Medicine Reports. 7, 1319-1323. Hu, C., Huang, Y., Su, J., Wang, M., Zhou, Q., Zhu, B., 2018. Detection and analysis of variants of JC polyomavirus in urine samples from HIV-1-infected patients in China's Zhejiang Province. The Journal of International Medical Research. 46, 1024-1032. Huang, G., Chen, L. Z., Qiu, J., Wang, C. X., Fei, J. G., Deng, S. X., Fu, Q., 2010. Prospective study of polyomavirus BK replication and nephropathy in renal transplant recipients in China: a single‐ center analysis of incidence, reduction in immunosuppression and clinical course. Clinical Transplantation. 24, 599-609. Hussain. I., Tasneem. F., Under. M., Pervaiz. A., Raza. M., Arshad. M. I., Shahzad. N., 2017. Specific and quantitative detection of human polyomaviruses, BKPyV and JCPyV in the healthy Pakistani population. Virology Journal. 14, 86. Ikegaya, H., Saukko, P. J., Tertti, R., Metsärinne, K. P., Carr, M. J., Crowley, B., 2006. Identification of genomic subgroup of BK polyomavirus spread in European populations. Journal of General Virology. 87, 3201-3208. Jagannath, S., Sachithanandham, J., Ramalingam, V. V., Demosthenes, J. P., Abraham, A. M., Zachariah, A., Varghese, G. M., Kannangai, R., 2018. BK virus characterisation among HIV-1-Infected individuals and its association with immunosuppression. Indian Journal of Medical Microbiology. 36, 172-177. Jasim, M. B., Al-Saedi, A. J. H., Hussein, M. R., Al-Obaidi, A., Kadhim, H. S., 2017. High prevalence of John Cunningham viruria in renal transplant recipients. Iraqi Journal of Medical Sciences. 15, 108-115. Jeong, B. H., Lee, K. H., Choi, E. K., Kim, K., Kim, Y. S., 2004. Genotyping of the JC virus in urine samples of healthy Korean individuals. Journal of Medical Virology. 72, 281-289. Johannessen, M., Walquist, M., Gerits, N., Dragset, M., Spang, A. and Moens, U., 2011.. BKV Agnoprotein Interacts with α-Soluble N-Ethylmaleimide-Sensitive Fusion Attachment Protein, and Negatively Influences Transport of VSVG-EGFPP. LoS One. 6: e24489. Imperiale, M., Major, E., 2007. Polyomaviruses, in: Knipe, D. M., Howley, P. M. (Eds.), Fields Virology, vol. fifth. Lippincott Williams and Wilkins, Philadelphia, pp. 2263-2298. Kadambi, PV., Josephson, M. A., Williams, J., Corey, L., Jerome, K. R., Meehan, S. M., Limaye, A. P., 2003. Treatment of refractory BK virus-associated nephropathy with cidofovir. American Journal of Transplantation. 3, 186-191. 20

Jo

ur na

lP

re

-p

ro

of

Kamminga, S., van der Meijden, E., Feltkamp, M. C. W., Zaaijer, H. L., 2018. Seroprevalence of fourteen human polyomaviruses determined in blood donors. PLoS ONE. 13, e0206273. Kaneko, T., Moriyama, T., Tsubakihara, Y., Horio, M., Imai, E., 2005. Prevalence of human polyoma virus (BK virus and JC virus) infection in patients with chronic renal disease. Clinical and Experimental Nephrology. 9, 132-137. Kaydani, G. A., Makvandi, M., Samarbafzadeh, A., Shahbazian, H., Fard, M. H., 2015. Prevalence and distribution of BK virus subtypes in renal transplant recipients referred to Golestan Hospital in Ahvaz, Iran. Jundishapur Journal of Microbiology.8, e16738. Kean, J. M., Rao, S., Wang, M., Garcea, R. L., 2009. Seroepidemiology of human polyomaviruses. PLoS pathogens, 5, e1000363. Krumbholz, A., Bininda-Emonds, O. R., Wutzler, P., Zell, R., 2008. Evolution of four BK virus subtypes. Infection, Genetics and Evolution. 8, 632-643. Lamdhade, S., Ashkanani, A., Alroughani, R., 2014. Prevalence of anti-JC virus antibody in multiple sclerosis patients in Kuwait. ISRN Neurology. 861091. Lau, A., Qiu, W., Kermode, A., Au, C., Ng, A., Wong, A., Ma, S., Au, L., Ma, K., Ip, B., Mok, V, 2018. High prevalence and indexes of anti-John Cunningham virus antibodies in a cohort of Chinese patients with multiple sclerosis. Multiple Sclerosis JournalExperimental, Translational and Clinical. 4, 2055217318788699. Lin, P. Y., Fung, C. Y., Chang, F. P., Huang, W. S., Chen, W. C., Wang, J. Y., Chang, D., 2008. Prevalence and genotype identification of human JC virus in colon cancer in Taiwan. Journal of Medical Virology. 80, 1828-1834. Low, J. A., Magnuson, B., Tsai, B., Imperiale, M. J., 2006. Identification of gangliosides GD1b and GT1b as receptors for BK virus. Journal of Virology. 80, 1361-1366. Marzocchetti, A., Lima, M., Tompkins, T., Kavanagh, D. G., Gandhi, R. T., O’Neill, D. W., Koralnik, I. J., 2009. Efficient in vitro expansion of JC virus-specific CD8+ T-cell responses by JCPyV peptide-stimulated dendritic cells from patients with progressive multifocal leukoencephalopathy. Virology. 383, 173-177. Matalka, I., Swedan, S., Khabaz, M. N.,Barahmeh, M., 2013. JC virus in colorectal cancer: where do we stand?. Future Virology. 8, 607-615. Mayberry, C. L., Soucy, A.N., Lajoie, C. R., DuShane, J. K., Maginnis, M. S., 2019. JC polyomavirus entry by clathrin mediated endocytosis is driven by -Arrestin. Journal of Virology. 93, e01948-18. Megged, O., Stein, J., Ben-Meir, D., Shulman, L. M., Yaniv, I., Shalit, I., Levy, I., 2011. BKvirus-associated hemorrhagic cystitis in children after hematopoietic stem cell transplantation. Journal of Pediatric Hematology/Oncology. 33, 190-193. Miranda, J. J., Takasaka, T., Zheng, H.-y., Kitamura, T., Yogo, Y., 2004. JC virus genotype profile in the Mamanwa, a Philippine Negrito tribe, and implications for its population history. Anthropological Science. 112, 173-178. Mou, X., Chen, L., Liu, F., Lin, J., Diao, P., Wang, H., Xiang, C., 2012. Prevalence of JC virus in Chinese patients with colorectal cancer. PloS One. 7, e35900. 21

Jo

ur na

lP

re

-p

ro

of

Nali, L. H. D. S., Centrone, C. D. C., Urbano, P. R. P., Penalva-de-Oliveira, A. C., Vidal, J. E., Miranda, E. P., Fink, M. C. D. D. S., 2012. High prevalence of the simultaneous excretion of polyomaviruses JC and BK in the urine of HIV-infected patients without neurological symptoms in São Paulo, Brazil. Revista do Instituto de Medicina Tropical de São Paulo. 54, 201-205. Neu, U., Maginnis, M. S., Palma, A. S., Stroh, L. J., Nelson, C. D., Feizi, T., Atwood, W. J., Stehle, T., 2010. Structure-function analysis of the human JC polyomavirus establishes the LSTcpentasaccharide as a functional receptor motif. Cell Host and Microbe. 8, 309-319. Panou, M. M., Prescott, E. L., Hurdiss, D. L., Swinscoe, G., Hollinshead, M., Caller, L. G., Macdonald, A.,2018. Agnoprotein Is an Essential Egress Factor during BK Polyomavirus Infection. International journal of molecular sciences, 19(3), 902. Pavesi, A., 2005. Utility of JC polyomavirus in tracing the pattern of human migrations dating to prehistoric times. Journal of General Virology. 86, 1315-1326. Pires, E. P., Bernardino‐ Vallinoto, C. V., Alves, D. M., Migone, S. R. C., Machado, L. F. A., Ishak, M. O. G., Vallinoto, A. C. R., 2011. Prevalence of infection by JC and BK polyomaviruses in kidney transplant recipients and patients with chronic renal disease. Transplant Infectious Disease. 13, 633-637. Pourjabari, K., Makvandi, M., Kaydani, G., Shahbazian, H., Samarbaf-Zadeh, A. R., 2016. Prevalence, reactivation and genotyping of John Cunningham virus among end-stage renal disease and kidney transplant patients. Future Virology. 11, 489-496. Prado, J., Monezi, T. A., Amorim, A. T., Lino, V., Paladino, A., Boccardo, E., 2018. Human polyomaviruses and cancer: an overview. Clinics (Sao Paulo, Brazil). 73, e558s. Qiao, L., Qu, Q., Jiang, X., 2016. Clinical significance of quantitative and qualitative detection of BK and JC virus in blood and urine of renal transplantation recipients. Pakistan Journal of Medical Sciences. 32, 435. Randhawa, P., Ho, A., Shapiro, R., Vats, A., Swalsky, P., Finkelstein, S., Weck, K., 2004. Correlates of quantitative measurement of BK polyomavirus (BKPyV) DNA with clinical course of BKPyV infection in renal transplant patients. Journal of Clinical Microbiology. 42, 1176-1180. Rinaldo, C. H., Tylden, G. D., Sharma, B. N., 2013. The human polyomavirus BK (BKPyV): virological background and clinical implications. Apmis. 121, 728-745. Rollison, D. E., Engels, E. A., Halsey, N. A., 2006. Pre diagnostic circulating antibodies to JC and BK human polyomaviruses and risk of non-Hodgkin lymphoma. Cancer Epidemiology, Biomarkers and Prevention. 15, 543–550. Sadeghi, F., Salehi-Vaziri, M., Ghodsi, S. M., Alizadeh, A., Bokharaei-Salim, F., Saroukalaei, S. T., Keyvani, H., 2015. Prevalence of JC polyomavirus large T antigen sequences among Iranian patients with central nervous system tumors. Archives of Virology. 160, 61-68. Shackelton, L. A., Rambaut, A., Pybus, O. G., Holmes, E. C., 2006. JC virus evolution and its association with human populations. Journal of Virology.80, 9928-9933.

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Shamran, H. A., Malik, S. N., Al-Saffer, J. M., Jawad, R. S., 2016. BK virus load associated with serum levels of sCD30 in renal transplant recipients. International Journal of Microbiology. 2016, 1-7. Shen, C. H., Wu, J. D., Hsu, C. D., Jou, Y. C., Lin, C. T., Wang, M., Fang, C. Y., 2011. The high incidence of JC virus infection in urothelial carcinoma tissue in Taiwan. Journal of Medical Virology. 83, 2191-2199. Silva, L. P., Patah, P. A., Saliba, R. M., Szewczyk, N. A., Gilman, L., Neumann, J., Han, X., Tarrand, J., Ribeiro, R., Gulbis, A., 2010. Hemorrhagic cystitis after allogeneic hematopoietic stem cell transplants is the complex result of BK virus infection, preparative regimen intensity and donor type. Haematologica. 95, 1183-1190. Singh, H. K., Bubendorf, L., Mihatsch, M. J., 2006. Urine cytology findings of polyomavirus infections. Advances in Experimental Medicine and Biology. 577, 201-212. Bhattacharjee, S., Chattaraj, S., 2017. Entry, infection, replication and egress of human polyomaviruses: an update. Canadian Journal of Microbiology. 63, 193-211. Takasaka, T., Goya, N., Tokumoto, T., Tanabe, K., Toma, H., Ogawa, Y., Fujioka, T., 2004. Subtypes of BK virus prevalent in Japan and variation in their transcriptional control region. Journal of General Virology, 85, 2821-2827. Tan, C. S., Koralink, I. J., 2009. JC, BK, and other polyomaviruses: progressive multifocal leukoencephalopathy. Mandell: Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases. seventhed. Churchill Livingstone: An Imprint of Elsevier. Thakur, R., Arora, S., Nada, R., Minz, M., Joshi, K., 2011. Prospective monitoring of BK virus reactivation in renal transplant recipients in North India. Transplant Infectious Disease. 13, 575-583. Toan, P. Q., Bao, L.T., Thu Hang, D. T., My Anh, T. T., Cuong, L. M., Lang, N. S., Su, H. X., 2019. Identification of BK Virus Genotypes in Recipients of Renal Transplant in Vietnam. Transplant proceedings. 51, 2683-2688. Tognon, M., &Provenzano, M., 2015. New insights on the association between the prostate cancer and the small DNA tumour virus, BK polyomavirus. Journal of translational medicine, 13, 387. Tsai, R.T., Wang, M., Ou, W.C., Lee, Y.L., Li, S.Y., Fung, C.Y., Huang, Y. L., Tzeng, T.Y., Chen, Y., Chang, D., 1997. Incidence of JC viruria is higher than that of BK viruria in Taiwan. Journal of medical virology. DOI:10.1002/(sici)10969071(199707)52:3<253::aid-jmv3>3.0.co;2-1. Tseng, C., Yeh, C., Fang, C., Shay, J., Chen, P., Lin, M., Wang, M., 2014. Detection of human JCPyV and BKPyV in diffuse large B-cell lymphoma of the GI tract. European Journal of Clinical Microbiology &Infectious Diseases. 33, 665-672. Vasudev, B., Hariharan, S., Hussain, S. A., Zhu, Y. R., Bresnahan, B. A., Cohen, E. P., 2005. BK virus nephritis: risk factors, timing, and outcome in renal transplant recipients. Kidney International. 68, 1834-1839.

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Verma, S., Cikurel, K., Koralnik, I. J., Morgello, S., Cunningham-Rundles, C., Weinstein, Z. R., Bergmann, C., Simpson, D. M., 2007. Mirtazapine in progressive multifocal leukoencephalopathy associated with polycythemia vera. The Journal of Infectious Diseases.196, 709-711. Wang, R. Y., Li, Y. J., Lee, W. C., Wu, H. H., Lin, C. Y., Lee, C. C., Tian, Y. C., 2016. The association between polyomavirus BK strains and BKV viruria in liver transplant recipients. Scientific reports, 6, 28491. Whiley, D. M., Mackay, I. M., Sloots, T. P., 2001. Detection and differentiation of human polyomaviruses JC and BK by Light Cycler PCR. Journal of Clinical Microbiology. 39, 4357-4361. Wittmann, T., Horowitz, N., Benyamini, N., Henig, I., Zuckerman, T., Rowe, J., Avivi, I., 2015. JC polyomavirus reactivation is common following allogeneic stem cell transplantation and its preemptive detection may prevent lethal complications. Bone Marrow Transplantation. 50, 984-991. Wong, A. S., Chan, K. H., Cheng, V. C., Yuen, K. Y., Kwong, Y. L., Leung, A.Y., 2007. Relationship of pre transplantation polyoma BK virus serologic findings and BK viral reactivation after hematopoietic stem cell transplantation. Clinical Infectious Diseases. 44, 830-837. Wu, J. K., Harris, M. T., 2008. Use of leflunomide in the treatment of polyomavirus BKassociated nephropathy. The Annals of Pharmacotherapy. 42, 1679-1685. Wunderink, H. F., De Brouwer, C. S., Gard, L., De Fijter, J. W., Kroes, A., Rotmans, J. I., Feltkamp, M., 2019. Source and relevance of the BK polyomavirus genotype for infection after kidney transplantation. Open Forum Infectious Diseases. 6, ofz078. Yoon, S.H., Cho, J.H., Jung, H.Y., Choi, J.Y., Park, S.H., Kim, Y.L., Kim, C.D., 2015. Clinical impact of BK virus surveillance on outcomes in kidney transplant recipients. Transplantation Proceedings. 47, 660-665. Zhong, S., Zheng, H.Y., Suzuki, M., Chen, Q., Ikegaya, H., Aoki, N., Yasuda, Y., 2007. Agerelated urinary excretion of BK polyomavirus by non-immunocompromised individuals. Journal of Clinical Microbiology. 45, 193-198. Zakaria, E. Z., Amir, M. E., Adel, A. G., Adel, I. B., Medhat, A. H., Osama, A. G., Ayman, M. N., Yahya, M., Mohamed, A. B., Mahmoud, M. M., Torki A., 2019. Screening for BK Viremia/Viruria and the Impact of Management of BK Virus Nephropathyin Renal Transplant Recipients. Experimental and Clinical Transplantation. 1: 83-91.

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Figure 1: The comparative analysis of BKPyV and JCPyV genomes. The genome organization of both BKPyV (A) and JCPyV (B) shows the early and late viral gene region separated by the regulatory non-coding control region (NCCR) containing numerous transcription factor binding sites. Arrow indicates the direction of gene transcription.

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Figure. 2. Schematic of BKPyV and JCPyV LT (Upper panel) and ST (Lower panel) proteins. The LT consists of J domain, linker domain, origin-binding domain (OBD), zinc finger motif, and helicase/ATPase domain. The ST presents a J domain and unique region, formed during the splicing process of LT.

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Figure 3: Primary target cells and reactivation sites of BKPyV (Left Panel) and JCPyV (Right Panel).

Figure 4. Schematic illustration of BKPyV and JCPyV life cycle.

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Figure 5: Categorization of Asian countries in terms of BKPyV prevalence.

Figure 6: Categorization of Asian countries in terms of JCPyV prevalence.

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Table 1: Overview and comparison of BKPyV and JCPyV viral proteins.

Early Region

Viral Proteins BKPyV

JCPyV

BKPyV

JCPyV

BKPyV

JCPyV

LT ST

LT ST T′165 T′136 T′135 VP1 VP2 VP3 Agnoprotein

Nucleus Nucleus

Nucleus Cytoplasm

695 172

Nucleus

Nucleus

135

Nucleus Nucleus Nucleus Cytoplasm

Nucleus Nucleus Nucleus Perinuclear

362 351 232 66

688 172 165 136 135 354 344 225 71

Trun TAg VP1 VP2 VP3 Agnoprotein

Mol. Wt. (KDa) BKPy V 80.5 20.5 17 40.1 38.3 26.7 7.4

JCPyV 79.3 20.2 18 15 14.8 39.6 37.4 25.7 8.1

Homology b/w BKPyV and JCPyV 83% 78%

63% 80% 77% 63%

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ro

Late Region

Cellular localization

No. of Amino Acids

of

Genome Region

Table 2: Geographic distribution of BKPyV and JCPyV subtypes. Subtypes 1, 4 & 5 2A 2B& 2C 2D 2E 3 6 7A, 7B & 7C 8

JCPyV Population European Japanese Eurasian Indian Australian South Africa central Africa Chinese and Asian Pacific Island

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Population All Rare Rare All

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BKPyV Subtypes I II III IV

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Table 3. Prevalence of BKPyV in Asian countries Country

Year of Study

Biological sample

Age group (years)

Method

Population under study

Prevalence (%)

Sample Size (n)

References

Kuwait

2013

20-56

PCR

Kidney Donors

3 7

165

qPCR

5.9% 5.3 (BK-HC) 30 24 22.6 14.7

1000 320

15

Chehadeh et al., 2013 Zakaria et al., 2019 Megged et al., 2011 Chen et al., 2006 Chen et al., 2006 Toan et al., 2019 Boobes et al ., 2015 Brown et al., 1975 Kaneko et al., 2005 Chen et al., 2006 Zhong et al., 2007 Funahashi et al., 2014

Mongolia Vietnam UAE

2006 2006 2019 2015

Malaysia

1975

>18

qPCR PCR qPCR qPCR

Blood

ELISA

Healthy

2005

Urine

PCR

2006

Urine

PCR

Healthy Renal disease Healthy

2007

Urine

PCR

2014

Serum Urine

1997

Urine

2013

Urine

2014

GI tract biopsy Urine

45-65

Serum

30-60

qPCR

Pregnant Autoimmune diseased Renal Transplant recipient Diffuse large B cell lymphoma Liver transplant recipient Renal transplant

Blood

25-55

qPCR PCR

0-89

PCR

24-78

Taiwan

2016 2018

India

2004

2011 2018

IHC

Urine

Jo

Iraq

qPCR

ur na

2016

qPCR

Urine Blood Urine

Pakistan

2017

Blood

China

2006 2010

Urine Blood

2016

Blood

22-68

10-80

Non Immunocompromise d Renal Transplant

qPCR

30 96 106 116

1544

13.5 33.3 25

37 45 104

27 13 65

450 270

3.9 6.2

77 48

20.4

250

31.5

16

77

22

22

50

Renal transplant

37

75

Pregnant Kidney disorder Renal transplant recipient Renal transplant

53.8 66 86.9

52 56 23 32 187 93

re

28-48 15-51

-p

IHC

lP

Japan

0-20

Renal transplant recipients Hematopoietic stem cell transplantation Healthy Healthy Renal Transplant Renal Transplant

of

2011

2019

ro

Israel

Blood Urine Blood Urine Tissue biopsy Urine Urine Urine Blood

Tsai et al., 1997 Hsieh et al., 2013

qPCR

HIV Infected Healthy

15.7 25 25 10.7

qPCR

Healthy

27.1

266

PCR PCR

Healthy Renal transplant

24.3 22.2

333 93

qPCR

Renal Transplant

33.3

306

>18

Tseng et al., 2014 Wang et al., 2016

Shamran et al., 2016 Al-Muaala et al., 2018 Bhattacharjee ]Chakraborty, 2004 Thakur et al., 2011 Jagannath et al., 2018 Hussain et al., 2017 Chen et al.,2006 Huang et al., 2010 Qiao et al., 2016

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Iran

2015

Urine

13-86

Korea

2015

Blood

PCR

Renal transplant

41.8

122

qPCR

Renal Transplant

66.7

213

Kaydani et al., 2015 Yoon et al., 2015

BKVAN: BK virus associated nephropathy; BK-HC: BKV associated Hemorrhagic Cystitis qPCR: quantitative real time PCR

Age group (years) 20-56

Method

Population under study

Prevalence (%)

Sample size (n)

References

PCR

Kidney donor

165

26-42

ELISA

MS

11 78 70

10-80

qPCR

Healthy

11.6

qPCR

Healthy

>17

PCR

AlloSCT

Urine

1-80

PCR

Healthy

20

100

2004

Urine

>40

PCR

Healthy

22

49

2012 2015

Urine Tumor tissue Urine

>18 11-83

PCR qPCR

re

Table 4. Prevalence of JCPyV in Asian countries

2013 2018

Blood Urine Blood

Healthy CNS tumor Renal Transplant ESRD

38.3 25.9 17.2

133 58 64

1.6

64

Healthy

18

250

Chehadeh et al., 2013 Alroughani et al., 2018 Hussain et al., 2017 Chattaraj et al., 2015 Wittmann et al., 2015 Jeong et al., 2004 Miranda et al., 2004 Bozorgi et al., 2012 Sadeghi et al., 2015 Pourjabari et al., 2016 Haghighi et al., 2019

Pakistan

2017

Blood

India

2015

Urine

Israel

2015

Blood

Korea

2004

Philippine

Chronic renal disease Healthy MS Colorectal cancer Normal HIV/PML HIV Healthy Renal transplant Healthy Renal Transplant

33.3

45

24.3 69 43.5

37 105 92

15.6 31 8.7 9.7 43.66

96 26 114 113 71

10 33.5 30.7

20 310 306

40.9

137

24.8 80

80 123

Iran 2016

Japan

Jordan

2005

Urine

2018 2013

2010

Jo

Thailand

Iraq

PBMC

20-59

PCR

ur na

2019

PCR

16-74

PCR

Blood Tissue

20-90

ELISA IHC PCR

CSF

>15

PCR

2017

Urine

2016

Blood Urine

>18

qPCR

2012

Tissue

27-86

Nested PCR

2018

Blood

>18

ELISA

China

qPCR

Colorectal cancer Healthy MS

168

of

Kuwait

266

ro

Biological sample

17.6

113

19

164

-p

Year

lP

Country

Kaneko et al., 2005 Aoyama et al., 2018 Matalka et al., 2013 Arunngamwong et al., 2010 Jasim et al., 2017 Qiao et al., 2016 Mou et al., 2012 Lau et al., 2018

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Taiwan

1997

Urine

2008

Tissue

>40

PCR

Healthy Pregnant Autoimmune Colon cancer

40-86

Nested PCR

Urothelial carcinoma

33.3 26 37.5 86.4

75 77 48 22

Tsai et al., 1997

90.1

33

Shen et al., 2011

Lin et al., 2008

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of

2011

PCR

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