Abstract
Xenotropic murine leukemia virus (MLV)-related virus (XMRV) is a new human retrovirus associated with prostate cancer and chronic fatigue syndrome. The causal relationship of XMRV infection to human disease and the mechanism of pathogenicity have not been established. During retrovirus replication, integration of the cDNA copy of the viral RNA genome into the host cell chromosome is an essential step and involves coordinated joining of the two ends of the linear viral DNA into staggered sites on target DNA. Correct integration produces proviruses that are flanked by a short direct repeat, which varies from 4 to 6 bp among the retroviruses but is invariant for each particular retrovirus. Uncoordinated joining of the two viral DNA ends into target DNA can cause insertions, deletions, or other genomic alterations at the integration site. To determine the fidelity of XMRV integration, cells infected with XMRV were clonally expanded and DNA sequences at the viral-host DNA junctions were determined and analyzed. We found that a majority of the provirus ends were correctly processed and flanked by a 4-bp direct repeat of host DNA. A weak consensus sequence was also detected at the XMRV integration sites. We conclude that integration of XMRV DNA involves a coordinated joining of two viral DNA ends that are spaced 4 bp apart on the target DNA and proceeds with high fidelity.
Highlights
Xenotropic murine leukemia virus (MLV)-related virus (XMRV) is a new human retrovirus having a 8.65 kbp genome and shares up to 95% overall nucleotide sequence identity with other known MLVs [1]
To determine the length of the target-site duplication during XMRV integration, we sequenced the stretches of host cell DNA flanking the long terminal repeat (LTR) at each end of a given provirus, and searched for these flanking sequences within the human genome
Examination of the viral DNA sequence of the provirus with the 273-bp target site duplication revealed that the left LTR contained a 5-bp deletion at the U3 end that includes a CA dinucleotide that is highly conserved in retroviruses [12]
Summary
Xenotropic murine leukemia virus (MLV)-related virus (XMRV) is a new human retrovirus having a 8.65 kbp genome and shares up to 95% overall nucleotide sequence identity with other known MLVs [1]. XMRV was first reported to be associated with prostate cancer from patients homozygous for a defective variant of RNase L (R462Q), a regulated endoribonuclease for single-stranded RNA that functions in the antiviral action of interferon (IFN) [1,2]. The causal relationships of XMRV infection to prostate cancer and chronic fatigue syndrome, as well as the mechanism for virus pathogenicity, have yet to be established. Several studies have failed to detect XMRV in different European cohorts of patients with either prostate cancer [8] or with chronic fatigue syndrome [9,10,11], suggesting that either population differences or environmental factors may modulate the incidence of XMRV infections
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