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No Evidence for an Association between JC Polyomavirus Infection and Gastroduodenal Diseases.

ABSTRACT: Background:Helicobacter pylori (HP) infection is one of the hypothesized infectious etiologies of gastric cancer (GC) and other gastroduodenal diseases. It was suggested that other infectious agents, including oncogenic viruses, may increase the risk of gastroduodenal diseases. A number of reports regarding JC polyomavirus (JCPyV) have shown that JCPyV could be implicated in colorectal cancer and gastrointestinal carcinogenesis. Objective:The current investigation aimed to investigate whether JCPyV could have any association with the pathogenesis of gastroduodenal diseases either alone or together with HP. Methods:A total of 237 fresh or formalin-fixed and paraffin-embedded gastroduodenal samples were examined by quantitative real-time polymerase chain reaction targeting the JCPyV large tumor antigen (LTag) oncogene, and viral load was determined as viral copy number/cell. Results:In total, 2 out of 237 samples (0.8%) were positive for JCPyV LTag DNA. One positive sample derived from diffuse-type gastric adenocarcinoma (6.8 × 10-3 copies/cell) and other JCPyV-positive sample obtained from a patient with gastritis (2.5 × 10-3 copies/cell) were recorded. Both JCPyV-positive samples were negative for HP infection. Conclusion:This study suggests no association between JCPyV infection and GC or other gastroduodenal diseases. The very low frequency of JCPyV LTag sequences in GC is an important aspect that weakens the hypothesis of the pathogenic role of JCPyV in gastric tumor induction.

SUBMITTER: Yazdani Cherati A

PROVIDER: S-EPMC6288631 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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No Evidence for an Association between JC Polyomavirus Infection and Gastroduodenal Diseases.

Yazdani Cherati Azadeh A Yahyapour Yousef Y Ranaee Mohammad M Rajabnia Mehdi M Shokri Shirvani Javad J Hajiahmadi Mahmoud M Sadeghi Farzin F

Gastrointestinal tumors 20180711 1-2

<h4>Background</h4><i>Helicobacter pylori</i> (HP) infection is one of the hypothesized infectious etiologies of gastric cancer (GC) and other gastroduodenal diseases. It was suggested that other infectious agents, including oncogenic viruses, may increase the risk of gastroduodenal diseases. A number of reports regarding JC polyomavirus (JCPyV) have shown that JCPyV could be implicated in colorectal cancer and gastrointestinal carcinogenesis.<h4>Objective</h4>The current investigation aimed to ...[more]

PMID: 30574481

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Project description:Progressive multifocal leukoencephalopathy (PML) is a fatal demyelinating disease of the central nervous system (CNS) caused by reactivation of the human polyomavirus JCV gene expression and its replication in oligodendrocytes, the myelin producing cells in the brain. Once a rare disease seen in patients with lymphotproliferative and myeloproliferative disorders, PML has been seen more frequently in HIV-1 positive/AIDS patients as well as patients undergoing immunomodulatory therapy due for autoimmune disorders including multiple sclerosis, rheumatoid arthritis, and others. As of now there is no cure for PML and in most cases disease progression leads to death within two years. Similar to other polyomaviruses, the JCV genome is small circular double stranded DNA that includes coding sequences for the viral early protein, T-antigen, which is critical for directing viral reactivation and lytic infection. Here, we employ a newly developed gene editing strategy, CRISPR/Cas9, to introduce mutations in the viral genome and, by inactivating the gene encoding T-antigen, inhibit viral replication. We first used bioinformatics screening and identified several potential targets within the JCV T-antigen gene that can serve as sites for the creation of guide RNAs (gRNAs) for positioning the Cas9 nuclease on the designated area of the viral genome for editing. Results from a series of integrated genetic and functional studies showed that transient or conditional expression of Cas9 and gRNAs specifically targets the DNA sequences corresponding to the N-terminal region of T-antigen, and by introducing mutation, interferes with expression and function of of the viral protein, hence suppressing viral replication in permissive cells. Results from SURVEYOR assay revealed no off-target effects of the JCV-specific CRISPR/Cas9 editing apparatus. These observations provide the first evidence for the employment of a gene editing strategy as a promising tool for the elimination of the JCV genome and a potential cure for PML.

Project description:JC polyomavirus (JCV) carriers with a compromised immune system, such as in HIV, or subjects on immune-modulating therapies, such as anti VLA-4 therapy may develop progressive multifocal leukoencephalopathy (PML) which is a lytic infection of oligodendrocytes in the brain. Serum antibodies to JCV mark infection occur only in 50-60% of infected individuals, and high JCV-antibody titers seem to increase the risk of developing PML. We here investigated the role of human leukocyte antigen (HLA), instrumental in immune defense in JCV antibody response. Anti-JCV antibody status, as a surrogate for JCV infection, were compared to HLA class I and II alleles in 1621 Scandinavian persons with MS and 1064 population-based Swedish controls and associations were replicated in 718 German persons with MS. HLA-alleles were determined by SNP imputation, sequence specific (SSP) kits and a reverse PCR sequence-specific oligonucleotide (PCR-SSO) method. An initial GWAS screen displayed a strong HLA class II region signal. The HLA-DRB1*15 haplotype was strongly negatively associated to JCV sero-status in Scandinavian MS cases (OR?=?0.42, p?=?7×10(-15)) and controls (OR?=?0.53, p?=?2×10(-5)). In contrast, the DQB1*06:03 haplotype was positively associated with JCV sero-status, in Scandinavian MS cases (OR?=?1.63, p?=?0.006), and controls (OR?=?2.69, p?=?1×10(-5)). The German dataset confirmed these findings (OR?=?0.54, p?=?1×10(-4) and OR?=?1.58, p?=?0.03 respectively for these haplotypes). HLA class II restricted immune responses, and hence CD4+ T cell immunity is pivotal for JCV infection control. Alleles within the HLA-DR1*15 haplotype are associated with a protective effect on JCV infection. Alleles within the DQB1*06:03 haplotype show an opposite association. These associations between JC virus antibody response and human leucocyte antigens supports the notion that CD4+ T cells are crucial in the immune defence to JCV and lays the ground for risk stratification for PML and development of therapy and prevention.

Dataset Information

No Evidence for an Association between JC Polyomavirus Infection and Gastroduodenal Diseases.

Publications

No Evidence for an Association between JC Polyomavirus Infection and Gastroduodenal Diseases.

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