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2007 PhD Retrovirus integration site selection and its biological significance

Discussion in 'XMRV Research and Replication Studies' started by leelaplay, Jan 16, 2010.

  1. leelaplay

    leelaplay member

    Dr. Marc-Alexander Fluks posted this to co-cure 2010 01 14

    Source: University of California, Los Angeles
    Date: 2007
    URL: d=79356&RQT=309&VName=PQD
    Rem: Ph.D. Thesis, 138 pages; ISBN: 9780549234111

    Retrovirus integration site selection and its biological significance
    by Kim, Sanggu, PhD

    Abstract (...)

    We have conducted integration site analysis for a recently identified Xenotropic murine leukemia virus-related virus (XMRV). XMRV is a previously undescribed gammaretrovirus that infects human cells. A strong correlation of XMRV infection with prostate cancer formation in patients who are homozygous for a RNase L variant has been shown.

    In this study, 472 XMRV integration sites in a human prostate cell line DU 145 were sequenced and compared to other retroviruses. Integration site selection of XMRV shares a largely conserved pattern with that of MLV and FV, but it also shows significantly higher preference for transcription start sites compared to the other retroviruses. The result suggests that XMRV integration into the genome may have strong genotoxicity for the host cell.

    Viruses have long been studied for the association with cancer. Recent identification of XMRV infection in prostate tissue from
    patients with variants in RNASEL, an innate antiviral agent and also one of hereditary prostate cancer genes, suggested a viral etiology in these patients. In this study, 16 XMRV integration sites in prostate cancer tissues from 8 patients who are homozygous for the RNASEL variant R462Q were sequenced and analyzed. The chromosomal regions hosting the 16 integration sites have a high correlation with prostate cancer development. Gene ontology study and cancer database search for the genes nearest to the 16 sites also showed a strong correlation with mechanisms involved in cancer formation.
    For comparison, genes near XMRV integration sites in acute infection and human cancer genes in Affymetrix G110 array were used. The results suggest a potential causative role of XMRV integration in prostate cancer formation.

    (c) 2007 University of California, Los Angeles
  2. very interesting
  3. natasa778

    natasa778 Senior Member

    There is also this interesting one:

    Viral sequence integration into introns of chemokine receptor genes

    Viral DNA sequences are able to integrate into the non-coding DNA sections of the genome of human cells which have been infected, either spontaneously or experimentally. We have made a data-base search for integration events of non-endogenous viruses into the introns of chemokine receptor sequences. A BLAST search of all viral DNA sequences, using the intronic sequences as Query, returned several significant alignments. However, due to the high reiteration rate of the non-coding sequences in the human genome, it became necessary to re-examine the individual alignments to verify whether the virus-flanking intronic sequence was really located in a chemokine receptor intron. We found only one unquestionable event of viral insertion of a section of a long terminal repeat of the murine leukemia virus within the first intron of the CC chemokine receptor 7 gene. Possible biological effects of such an insertion are discussed. Further experimental or clinical research could demonstrate the occurrence of other intronic viral insertions in human chemokine receptor genes. Maria Antonietta Panaro, Immunopharmacology and Immunotoxicology, December 2009, Vol. 31, No. 4, Pages 589-594

    Since chemokine receptors are crucial factors in all sorts of viral and bacterial infections it is not hard to imagine how messing up expression levels those genes would have widespread effects on host resistance and viral/bacterial virulence. For example certain chemokine receptor polymorphisms are thought to be central determinants of disease outcome in HIV infection, including its neurological consequence - NeuroAids (which btw means Autism when hits early in life all this downstream of chemokine receptor overactivation affecting membrane calcium trafficking).

    I do not have access to full paper but it would be interesting to read the parts where Possible biological effects of such an insertion are discussed.
  4. natasa778

    natasa778 Senior Member

    just came across this one, links in to my comments above:

    Homeostatic chemokines CCL19 and CCL21 promote inflammation in human immunodeficiency virus-infected patients with ongoing viral replication
    ... These findings link a dysregulated CCL19/CCL21/CCR7 system in HIV-infected patients to persistent inflammation and HIV replication, not only in untreated HIV infection, but also in treatment failure during HAART
  5. Judy Mikovits once said something about a test for 5 Cytokines and Chemokines.

    I wonder if this will come out for XMRV people and be available at VIPDX?

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