Investigation of human brain tumors for the presence of polyomavirus genome sequences by two independent laboratories

Rollison, Dana E.; Utaipat, Utaiwan; Ryschkewitsch, Caroline F.; Hou, Jean; Goldthwaite, Patricia T.; Daniel, Richard; Helzlsouer, Kathy J.; Burger, Peter C.; Shah, Keerti V.; Major, Eugene O.

doi:10.1002/ijc.20641

Cited by 81 publications

(51 citation statements)

References 33 publications

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“…However, it is not always been possible to interpret the significance of small numbers of polyomavirus sequences in human tumor tissues. 30,31 There were no indications of severe immunosuppression or asymptomatic BKV infection in the medical records of the BKV-positive cases.…”

Section: Discussionmentioning

confidence: 98%

Lack of BK virus DNA sequences in most transitional‐cell carcinomas of the bladder

Rollison¹,

Sexton²,

Rodríguez³

et al. 2006

Intl Journal of Cancer

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BK virus (BKV), a common human polyomavirus infection latent in the kidneys, can reactivate with immunosuppression to cause renal disease. Some have suggested that BKV may contribute to the development of bladder cancer, and BKV sequences have been reported from bladder tumors. To further examine the role of BKV in human bladder cancer, a series of bladder tumors was investigated for BKV genomic sequences. Fresh‐frozen specimens from 76 transitional cell carcinoma tissues and 46 paired adjacent normal urothelial tissues archived at the H. Lee Moffitt Cancer Center were studied. All tissues were histopathologically reviewed. DNA extracted from the tissues was tested by quantitative real‐time polymerase chain reaction (QPCR) assays to detect BKV DNA sequences in the VP1 coding region. Amplification of ERV‐3 was conducted separately to quantify cell copy number. Conventional PCR targeting the BKV T‐antigen (T‐Ag) coding region and immunohistochemistry for BKV T‐Ag were also conducted on all tissues that tested positive for BKV by QPCR. Seventy‐three bladder tumors yielded ≥3,000 copies of ERV‐3, 4 (5.5%) of which tested positive for BKV with average copy numbers of 7.9, 15.8, 0.4 and 0.3 per 1,000 cells. Paired normal tissue was available for 2 of these BKV‐positive tumors, 1 of which was BKV‐positive (14.6 copies/1,000 cells). No other normal tissues were BKV‐positive by QPCR. The 6 BKV‐positive tissues by QPCR were also positive by conventional PCR, but all stained negative for BKV T‐Ag by immunohistochemistry. BKV is unlikely to be involved in the etiology of most bladder tumors. © 2006 Wiley‐Liss, Inc.

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Section: Discussionmentioning

confidence: 98%

Lack of BK virus DNA sequences in most transitional‐cell carcinomas of the bladder

Rollison¹,

Sexton²,

Rodríguez³

et al. 2006

Intl Journal of Cancer

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“…[8][9][10][11] Of interest, PCR-based and immunohistochemical detection of the JC virus (JCV) genome and viral proteins, including JCV T-antigen, has raised questions about the contribution of this common polyomavirus to the development of medulloblastoma. [12][13][14][15] The genomic alterations and possible viral contribution suggest that mechanisms responsible for the maintenance of genomic integrity could be compromised in medulloblastomas. One feasible connection to the development of genomic instability is JCV Tantigen.…”

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confidence: 99%

IRS‐1–Rad51 nuclear interaction sensitizes JCV T‐antigen positive medulloblastoma cells to genotoxic treatment

Trojanek

Croul

et al. 2006

Intl Journal of Cancer

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The large T-antigen from human polyomavirus JC (JCV T-antigen) is suspected to play a role in malignant transformation. Previously, we reported that JCV T-antigen requires the presence of a functional insulin-like growth factor I receptor (IGF-IR) for transformation of fibroblasts and for survival of medulloblastoma cell lines; that IGF-IR is phosphorylated in medulloblastoma biopsies and that JCV T-antigen inhibits homologous recombinationdirected DNA repair, causing accumulation of mutations. Here we are evaluating whether JCV T-antigen positive and negative mouse medulloblastoma cell lines, which significantly differ in their tumorigenic properties, are also different in their abilities to repair double strand breaks of DNA (DSBs). Our results show that despite much stronger tumorigenic potential, JCV T-antigen positive medulloblastoma cells are more sensitive to genotoxic agents (cisplatin and c-irradiation). Subsequent analysis of DNA repair of DSBs indicated that homologous recombination-directed DNA repair (HRR) was selectively attenuated in JCV T-antigen positive medulloblastoma cells. JCV T-antigen did not affect HRR directly. In the presence of JCV T-antigen, insulin receptor substrate 1 (IRS-1) translocated to the nucleus where it co-localized with Rad51, possibly attenuating HRR. ' 2006 Wiley-Liss, Inc.

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“…There is substantial evidence on persistency of JCV in the CNS 44, 45, 46, 47. A recent study in immunocompetent non‐PML patients detected fragments of JCV DNA in brain oligodendrocytes and astrocytes, but not in neurons 47.…”

Section: Discussionmentioning

confidence: 99%

TLR3 agonism re‐establishes CNS immune competence during α4‐integrin deficiency

Hussain

Cravens

Doelger

et al. 2018

Ann Clin Transl Neurol

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ObjectiveNatalizumab blocks α4‐integrin‐mediated leukocyte migration into the central nervous system (CNS). It diminishes disease activity in multiple sclerosis (MS), but carries a high risk of progressive multifocal encephalopathy (PML), an opportunistic infection with JV virus that may be prompted by diminished CNS immune surveillance. The initial host response to viral infections entails the synthesis of type I interferons (IFN) upon engagement of TLR3 receptors. We hypothesized that TLR3 agonism reestablishes CNS immune competence in the setting of α4‐integrin deficiency.MethodWe generated the conditional knock out mouse strain Mx1.Cre+ α4‐integrinfl/fl, in which the α4‐integrin gene is ablated upon treatment with the TLR3 agonist poly I:C. Adoptive transfer of purified lymphocytes from poly I:C‐treated Mx1.Cre+ α4‐integrinfl/fl donors into naive recipients recapitulates immunosuppression under natalizumab. Active experimental autoimmune encephalomyelitis (EAE) in Mx1.Cre+ α4‐integrinfl/fl mice treated with poly I:C represents immune‐reconstitution.ResultsAdoptive transfer of T cells from poly I:C treated Mx1.Cre+ α4‐integrinfl/fl mice causes minimal EAE. The in vitro migratory capability of CD45+ splenocytes from these mice is reduced. In contrast, actively‐induced EAE after poly I:C treatment results in full disease susceptibility of Mx1.Cre+ α4‐integrinfl/fl mice, and the number and composition of CNS leukocytes is similar to controls. Extravasation of Evans Blue indicates a compromised blood‐brain barrier. Poly I:C treatment results in a 2‐fold increase in IFN β transcription in the spinal cord.InterpretationOur data suggest that TLR3 agonism in the setting of relative α4‐integrin deficiency can reestablish CNS immune surveillance in an experimental model. This pathway may present a feasible treatment strategy to treat and prevent PML under natalizumab therapy and should be considered for further experimental evaluation in a controlled setting.

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Investigation of human brain tumors for the presence of polyomavirus genome sequences by two independent laboratories

Cited by 81 publications

References 33 publications

Lack of BK virus DNA sequences in most transitional‐cell carcinomas of the bladder

Lack of BK virus DNA sequences in most transitional‐cell carcinomas of the bladder

IRS‐1–Rad51 nuclear interaction sensitizes JCV T‐antigen positive medulloblastoma cells to genotoxic treatment

TLR3 agonism re‐establishes CNS immune competence during α4‐integrin deficiency

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