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Polyomavirus BK with rearranged noncoding control region emerge in vivo in renal transplant patients and increase viral replication and cytopathology.

ABSTRACT: Immunosuppression is required for BK viremia and polyomavirus BK-associated nephropathy (PVAN) in kidney transplants (KTs), but the role of viral determinants is unclear. We examined BKV noncoding control regions (NCCR), which coordinate viral gene expression and replication. In 286 day-matched plasma and urine samples from 129 KT patients with BKV viremia, including 70 with PVAN, the majority of viruses contained archetypal (ww-) NCCRs. However, rearranged (rr-) NCCRs were more frequent in plasma than in urine samples (22 vs. 4%; P < 0.001), and were associated with 20-fold higher plasma BKV loads (2.0 x 10(4)/ml vs. 4.4 x 10(5)/ml; P < 0.001). Emergence of rr-NCCR in plasma correlated with duration and peak BKV load (R(2) = 0.64; P < 0.001). This was confirmed in a prospective cohort of 733 plasma samples from 227 patients. For 39 PVAN patients with available biopsies, rr-NCCRs were associated with more extensive viral replication and inflammation. Cloning of 10 rr-NCCRs revealed diverse duplications or deletions in different NCCR subregions, but all were sufficient to increase early gene expression, replication capacity, and cytopathology of recombinant BKV in vitro. Thus, rr-NCCR BKV emergence in plasma is linked to increased replication capacity and disease in KTs.

SUBMITTER: Gosert R

PROVIDER: S-EPMC2292223 | biostudies-literature | 2008 Apr

REPOSITORIES: biostudies-literature

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Polyomavirus BK with rearranged noncoding control region emerge in vivo in renal transplant patients and increase viral replication and cytopathology.

Gosert Rainer R Rinaldo Christine H CH Funk Georg A GA Egli Adrian A Ramos Emilio E Drachenberg Cinthia B CB Hirsch Hans H HH

The Journal of experimental medicine 20080317 4

Immunosuppression is required for BK viremia and polyomavirus BK-associated nephropathy (PVAN) in kidney transplants (KTs), but the role of viral determinants is unclear. We examined BKV noncoding control regions (NCCR), which coordinate viral gene expression and replication. In 286 day-matched plasma and urine samples from 129 KT patients with BKV viremia, including 70 with PVAN, the majority of viruses contained archetypal (ww-) NCCRs. However, rearranged (rr-) NCCRs were more frequent in plas ...[more]

PMID: 18347101

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Project description:Introduction: Viremia after renal transplantation is a major cause of morbidity and mortality and treatment opportunities are limited. Tests to determine the increased risk for viremia would be preferable.Methods: In a prospective, single-center study, we conducted follow-up of 163 renal transplant recipients after incident living donor renal transplantation. We determined a long noncoding RNA, ?-1,4-mannosylglycoprotein 4-?-N-acetylglucosaminyltransferase-antisense1 (MGAT3-AS1/beta-actin ratio), in peripheral blood mononuclear cells. Viremia of BK polyomavirus and cytomegalovirus was diagnosed with more than 1000 plasma copies/ml within the first 3 postoperative months. The MGAT3-AS1/beta-actin ratio was assessed before viremia was determined.Results: Receiver operator characteristics curve analysis showed a median MGAT3-AS1/beta-actin ratio cutoff value of 4.45 × 10-6 to indicate viremia after transplantation. Samples for 11 of 66 renal transplant recipients (17%) with MGAT3-AS1/beta-actin ratios below 4.45 × 10-6 showed viremia of BK polyomavirus and cytomegalovirus compared with only 6 of 97 renal transplant recipients (6%) with higher MGAT3-AS1/beta-actin ratios (odds ratio [OR]: 3.03; 95% confidence interval [CI]: 1.06-8.67 by Fisher exact test). Furthermore, samples for 6 of 66 renal transplant recipients (9%) with MGAT3-AS1/beta-actin ratios below 4.45 × 10-6 showed BK polyomavirus viremia compared with none of 97 renal transplant recipients (0%) with higher MGAT3-AS1/beta-actin ratios (OR: 20.95; 95% CI, 1.16-378.85 by Fisher exact test). Multivariate logistic regression analysis confirmed that MGAT3-AS1/beta-actin ratios below the cutoff level remained significantly associated with viremia after transplant. Lower MGAT3-AS1/beta-actin ratios occurred with rituximab-containing induction therapy.Conclusions: A low MGAT3-AS1/beta-actin ratio indicates an increased risk for viremia of BK polyomavirus and cytomegalovirus in living donor renal transplant recipients.

Project description:UnlabelledIn 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. Group 3 mutations decreased early and late gene expression and included two other Sp1 sites near the early TSS. Recombinant viruses bearing group 1 NCCRs showed increased replication in human renal epithelial cells similar to clinical rr-NCCR variants. Group 2 and 3 viruses showed intermediate or no replication, respectively. A literature search revealed unnoticed group 1 mutations in BKPyV nephropathy, hemorrhagic cystitis, and disseminated disease.ImportanceThe NCCRs of polyomaviruses mediate silent persistence of the viral genome as well as the appropriately timed (re)activation of the viral life cycle. This study indicates that the basal BKPyV NCCR is critically controlled by a hierarchy of single TFBS in the archetype NCCR that direct, modulate, and execute the bidirectional early and late viral gene expression. The results provide new insights into how BKPyV NCCR functions as a viral sensor of host cell signals and shed new light on how transcription factors like Sp1 control bidirectional viral gene expression and contribute to replication and pathology.

Dataset Information

Polyomavirus BK with rearranged noncoding control region emerge in vivo in renal transplant patients and increase viral replication and cytopathology.

Publications

Polyomavirus BK with rearranged noncoding control region emerge in vivo in renal transplant patients and increase viral replication and cytopathology.

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