Human Polyomavirus 7-Associated Pruritic Rash and Viremia in Transplant Recipients

Ho, Jonhan; Jedrych, Jaroslaw; Feng, Huichen; Natalie, August A.; Grandinetti, Lisa M.; Mirvish, Ezra D.; Crespo, Maria; Yadav, Dhiraj; Fasanella, Kenneth E.; Proksell, Siobhan; Kuan, Shih Fan; Pastrana, Diana V.; Buck, Christopher B.; Shuda, Yoko; Moore, Patrick S.; Chang, Yuan

doi:10.1093/infdis/jiu524

Cited by 89 publications

(110 citation statements)

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“…This includes silent persistence of the episomal viral genome and the appropriately timed (re)activation of the PyV life cycle, consisting of EVGR expression followed by viral genome replication and LVGR expression to generate infectious progeny. Besides a principle virological interest in the mechanisms mediating these functions within less than 400 base pairs (35), there is a strong clinical interest, since NCCR rearrangements have been associated with major human PyV pathologies, i.e., BKPyV-associated nephropathy and JCPyV progressive multifocal leukoencephalopathy (8,13,18,25,36,37) and more recently an HPyV-7-associated proliferative keratinocytic skin disease (38). However, the multitude of TFBS and their considerable diversity in clinically identified NCCR rearrangements has hampered identification of their specific role in PyV biology and human pathology.…”

Section: Discussionmentioning

confidence: 99%

Sp1 Sites in the Noncoding Control Region of BK Polyomavirus Are Key Regulators of Bidirectional Viral Early and Late Gene Expression

Bethge

Hachemi

Manzetti

et al. 2015

J Virol

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In kidney transplant patients with BK polyomavirus (BKPyV) nephropathy, viral variants arise bearing rearranged noncoding control regions (rr-NCCRs) that increase viral early gene expression, replicative fitness, and cytopathology. rr-NCCRs result from various deletions and duplications of archetype NCCR (ww-NCCR) sequences, which alter transcription factor binding sites (TFBS). However, the role of specific TFBS is unclear. We inactivated 28 TFBS in the archetype NCCR by selective point mutations and examined viral gene expression in bidirectional reporter constructs. Compared to the archetype, group 1 mutations increased viral early gene expression similar to rr-NCCR and resulted from inactivating one Sp1 or one Ets1 TFBS near the late transcription start site (TSS). Group 2 mutations conferred intermediate early gene activation and affected NF1, YY1, and p53 sites between early and late TSS. BK polyomavirus (BKPyV) is one of now more than 12 human PyVs (1) and is known to infect more than 90% of the human population during early childhood (2-6). Following primary infection, BKPyV persists latently in the renourinary tract, with intermittent periods of asymptomatic shedding into urine (5, 7). BKPyV disease typically occurs in individuals with altered immune functions, to which viral determinants are thought to contribute (3, 8). Thus, BKPyV causes nephropathy in 1 to 14% of kidney transplant patients and hemorrhagic cystitis in 5 to 20% of allogeneic hematopoietic stem cell transplant recipients (2, 9).BKPyV strains excreted in urine of healthy immunocompetent individuals typically bear a noncoding control region (NCCR) of linear archetype (ww) architecture (ww-NCCR) (5, 10, 11) and grow slowly in primary human urothelial and renal tubular epithelial cells (8,12). In immunosuppressed kidney transplant patients with early stages of BKPyV-associated nephropathy, the virus contains mostly archetype ww-NCCR (8, 13). However, when immunosuppression is not readily reduced to permit specific T cells to resume control over BKPyV replication (14-17), viral variants with rearranged NCCRs (rr-NCCRs) emerge that are associated with higher plasma viral loads and more severe renal allograft pathology (8). Similar rr-NCCRs of JC polyomavirus have been linked with the emergence of progressive multifocal leukoencephalopathy, a debilitating, often fatal brain disease in immunocompromised patients with HIV/AIDS or receiving transplantation or therapies for cancer and immune diseases (18)(19)(20)(21)(22). The archetype NCCR of polyomaviruses is approximately 400 bp in length and harbors the origin of replication as well as bidirectional promoter/ enhancer functions that, in concert with the host cell signals, control the timing and sequential activation of early viral gene region (EVGR) expression, viral DNA genome replication, and late viral gene region (LVGR) expression. Notably, EVGR and LVGR are encoded and transcribed in opposite directions from the NCCR (23). The ϳ2.3-kb EVGR encodes the small T antigen, the large ...

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Section: Discussionmentioning

confidence: 99%

Sp1 Sites in the Noncoding Control Region of BK Polyomavirus Are Key Regulators of Bidirectional Viral Early and Late Gene Expression

Bethge

Hachemi

Manzetti

et al. 2015

J Virol

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“…BKPyV is associated with nephropathy in renal transplant patients and with haemorrhagic cystitis in bone marrow recipients (Hirsch & Steiger, 2003), while JCPyV is the aetiological agent of progressive multifocal leukoencephalopathy (Tan & Koralnik, 2010 cause of 80 % of Merkel cell carcinoma (Feng et al, 2008), while TSPyV is linked to the rare skin disease trichodysplasia spinulosa in immunocompromised patients (van der Meijden et al, 2010). HPyV7 DNA was discovered in peripheral blood of two and in gastric mucosal tissues of one of two lung transplant patients who developed pruritic rash, and DNA and large T-antigen expression was found to be common in thymomas (23/37) and thymic hyperplasias (8/20) (Ho et al, 2015;Rennspiess et al, 2015). Whether the other HPyVs contribute to diseases is not known (DeCaprio & Garcea, 2013).…”

Section: Introductionmentioning

confidence: 99%

Early and late promoters of BK polyomavirus, Merkel cell polyomavirus, Trichodysplasia spinulosa-associated polyomavirus and human polyomavirus 12 are among the strongest of all known human polyomaviruses in 10 different cell lines

Moens

Ghelue

Ludvigsen

et al. 2015

Journal of General Virology

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Early and late promoters of BK polyomavirus, Merkel cell polyomavirus, Trichodysplasia spinulosa-associated polyomavirus and human polyomavirus 12 are among the strongest of all known human polyomaviruses in 10 different cell lines Little is known about cell tropism of the novel HPyVs, and cell cultures allowing virus propagation are lacking. Because viral tropism partially depends on the interaction of cellular transcription factors with the viral promoter, we monitored the promoter activity of all known HPyVs. Therefore, we compared the relative early and late promoter activity of the BK polyomavirus (BKPyV) (WW strain) with the corresponding activities of the other HPyVs in 10 different cell lines derived from brain, colon, kidney, liver, lung, the oral cavity and skin. Our results show that the BKPyV, MCPyV, TSPyV and HPyV12 early promoters displayed the strongest activity in most cell lines tested, while the remaining HPyV had relative low early promoter activity. HPyV12 showed the highest late promoter activity of all HPyVs in most cell lines, but also the BKPyV, MCPyV and TSPyV late promoters belonged to the stronger ones among HPyVs. The HPyVs with weak early promoter activity had in general also weak late promoter activity, except for HPyV10 whose late promoter was relatively strong in six of the 10 cell lines. A 20 bp deletion in the promoter of an HPyV12 variant significantly affected both early and late promoter activity in most cell lines. In conclusion, our findings suggest which cell lines may be suitable for virus propagation and may give an indication of the cell tropism of the HPyVs.

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“…For example, although WU polyomavirus (WUPyV) (6) and KI polyomavirus (KIPyV) (7) were isolated from nasopharyngeal secretions of children, they do not appear to contribute to pneumonia or other pulmonary disorders. HPyV6 (8) and HPyV7 (8) were found to be chronically shed from the skin; HPyV7 was recently associated with a pruritic rash in certain immunocompromised individuals (9). HPyV9 (10) was found in blood and urine and has sequence similarity to the B-lymphotropic polyomavirus previously isolated from African green monkey cells (11).…”

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confidence: 97%

Malawi Polyomavirus Is a Prevalent Human Virus That Interacts with Known Tumor Suppressors

Berrios

Jung

Primi

et al. 2015

J Virol

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h Malawi polyomavirus (MWPyV) is a recently identified human polyomavirus. Serology for MWPyV VP1 indicates that infection frequently occurs in childhood and reaches a prevalence of 75% in adults. The MWPyV small T antigen (ST) binds protein phosphatase 2A (PP2A), and the large T antigen (LT) binds pRb, p107, p130, and p53. However, the MWPyV LT was less stable than the simian virus 40 (SV40) LT and was unable to promote the growth of normal cells. This report confirms that MWPyV is a widespread human virus expressing T antigens with low transforming potential. Polyomaviruses are small, nonenveloped, circular doublestranded DNA viruses that maintain persistent lifelong infections in humans and animals (1). Human polyomaviruses (HPyV), including JC polyomavirus (JCPyV) and BK polyomavirus (BKPyV), can cause significant disease, primarily in immunocompromised individuals, with increased virus levels contributing to the progression of a disease state (1, 2). Since 2007, the identification of 11 new HPyV has brought renewed attention to this family of DNA tumor viruses and their potential role in human disease. For example, trichodysplasia spinulosa-associated polyomavirus (TSPyV) was isolated from severely immunocompromised patients with trichodysplasia spinulosa (3). The Merkel cell polyomavirus (MCPyV) was found to be clonally integrated into a large percentage of Merkel cell carcinomas (MCC), a cancer with risk factors that include advanced age, prolonged UV exposure, and immunosuppression due to HIV-1/AIDS, hematologic malignancy, or solid-organ transplantation (4, 5). However, many new HPyV have not yet been associated with disease. For example, although WU polyomavirus (WUPyV) (6) and KI polyomavirus (KIPyV) (7) were isolated from nasopharyngeal secretions of children, they do not appear to contribute to pneumonia or other pulmonary disorders. HPyV6 (8) and HPyV7 (8) were found to be chronically shed from the skin; HPyV7 was recently associated with a pruritic rash in certain immunocompromised individuals (9). HPyV9 (10) was found in blood and urine and has sequence similarity to the B-lymphotropic polyomavirus previously isolated from African green monkey cells (11).Malawi polyomavirus (MWPyV) (12), Saint Louis polyomavirus (STLPyV) (13), HPyV12 (14), and New Jersey polyomavirus (NJPyV) (15) are the most recently described HPyV. HPyV12 was isolated from resected human liver tissue, while NJPyV was found in endothelial cells of a pancreatic transplant patient. HPyV10 (16) and Mexico polyomavirus (MXPyV) (17) represent different isolates of MWPyV, while STLPyV, HPyV12, and NJPyV are genetically distinct HPyV species. MWPyV/MXPyV and STLPyV were isolated from human stool samples in children presenting with diarrhea. MWPyV and HPyV10 were also isolated from a wart in a patient with WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome. WHIM syndrome increases patient susceptibility to human papillomavirus (HPV) infection (18). It is possible that MWPyV/HPyV10 contributed to the development ...

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Human Polyomavirus 7-Associated Pruritic Rash and Viremia in Transplant Recipients

Cited by 89 publications

References 14 publications

Sp1 Sites in the Noncoding Control Region of BK Polyomavirus Are Key Regulators of Bidirectional Viral Early and Late Gene Expression

Sp1 Sites in the Noncoding Control Region of BK Polyomavirus Are Key Regulators of Bidirectional Viral Early and Late Gene Expression

Early and late promoters of BK polyomavirus, Merkel cell polyomavirus, Trichodysplasia spinulosa-associated polyomavirus and human polyomavirus 12 are among the strongest of all known human polyomaviruses in 10 different cell lines

Malawi Polyomavirus Is a Prevalent Human Virus That Interacts with Known Tumor Suppressors

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