Human Adenovirus, Polyomavirus, and Parvovirus Infections in Patients Undergoing Hematopoietic Stem Cell Transplantation

Hirsch, Hans H.; Pergam, Steven A.

doi:10.1002/9781118416426.ch93

Cited by 13 publications

(20 citation statements)

References 182 publications

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“…ADV infection is mostly mild or asymptomatic in immunocompetent persons. In transplant patients, however, ADV may cause severe local and invasive end‐organ diseases including hemorrhagic cystitis, nephritis, pneumonia, hepatitis and gastroenteritis, leading to life‐threatening disseminated disease affecting multiple organs . Current therapeutic recommendations generally emphasize intravenous cidofovir and reducing immunosuppression ; however, an orally administered lipid conjugate of cidofovir with higher potency is being developed for clinical use .…”

Section: Introductionmentioning

confidence: 99%

The “ABC” of Virus-Specific T Cell Immunity in Solid Organ Transplantation

Sester

Leboeuf

Schmidt

et al. 2016

American Journal of Transplantation

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Transplant patients are at increased risk of viral complications due to impaired control of viral replication, resulting from HLA mismatching between graft and host and the immunosuppression needed to avert alloimmune reactions. In the past decade, quantitative viral load measurements have become widely available to identify patients at risk and to inform treatment decisions with respect to immunosuppressive drugs and antiviral therapies. Because viral loads are viewed as the result of viral replication and virus‐specific immune control, virus‐specific T cell monitoring has been explored to optimize management of adenovirus, BK polyomavirus and cytomegalovirus (“ABC”) in transplant patients. Although most studies are descriptive using different technologies, the overall results show that the quantity and quality of virus‐specific T cells inversely correlate with viral replication, whereby strong cellular immune responses are associated with containment of viral replication. The key obstacles to the introduction of assays for virus‐specific T cells into clinical practice is the definition of reliable cutoffs for clinical decision making, the poor negative predictive value of some assays, and the absence of interventional trials justifying changes of antiviral treatment or immunosuppression. More clinical research is needed using optimized assays and targets before standardization and commutability can be envisaged as achieved for viral load testing.

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Section: Introductionmentioning

confidence: 99%

The “ABC” of Virus-Specific T Cell Immunity in Solid Organ Transplantation

Sester

Leboeuf

Schmidt

et al. 2016

American Journal of Transplantation

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“…Immunosuppression, which is commonly administered posttransplantation, has been shown to relax the adaptive antiviral immune control (13)(14)(15)(16) and to permit high-level replication with median urine BKPyV loads of over 7 log 10 copies/ml that become apparent as decoy cell shedding in urine (15)(16)(17)(18)(19)(20). Progression to BKPyV disease is most consistently encountered as nephropathy in 1 to 15% of kidney transplant recipients (21)(22)(23) or as hemorrhagic cystitis in 5 to 20% of allogeneic hematopoietic stem cell transplant recipients (24)(25)(26).…”

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confidence: 99%

Imperfect Symmetry of Sp1 and Core Promoter Sequences Regulates Early and Late Virus Gene Expression of the Bidirectional BK Polyomavirus Noncoding Control Region

Bethge

Ajuh

Hirsch

2016

J Virol

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Rearrangements or point mutations in the noncoding control region (NCCR) of BK polyomavirus (BKPyV) have been associated with higher viral loads and more pronounced organ pathology in immunocompromised patients. The respective alterations affect a multitude of transcription factor binding sites (TFBS) but consistently cause increased expression of the early viral gene region (EVGR) at the expense of late viral gene region (LVGR) expression. By mutating TFBS, we identified three phenotypic groups leading to strong, intermediate, or impaired EVGR expression and corresponding BKPyV replication. Unexpectedly, Sp1 TFBS mutants either activated or inhibited EVGR expression when located proximal to the LVGR (sp1-4) or the EVGR (sp1-2), respectively. We now demonstrate that the bidirectional balance of EVGR and LVGR expression is dependent on affinity, strand orientation, and the number of Sp1 sites. Swapping the LVGR-proximal high-affinity SP1-4 with the EVGR-proximal low-affinity SP1-2 in site strand flipping or inserting an additional SP1-2 site caused a rearranged NCCR phenotype of increased EVGR expression and faster BKPyV replication. The 5= rapid amplification of cDNA ends revealed an imperfect symmetry between the EVGR-and LVGR-proximal parts of the NCCR, consisting of TATA and TATA-like elements, initiator elements, and downstream promoter elements. Mutation or deletion of the archetypal LVGR promoter, which is found in activated NCCR variants, abrogated LVGR expression, which could be restored by providing large T antigen (LTag) in trans. Thus, whereas Sp1 sites control the initial EVGR-LVGR expression balance, LTag expression can override inactivation of the LVGR promoter and acts as a key driver of LVGR expression independently of the Sp1 sites and core promoter elements. IMPORTANCEPolyomaviridae currently comprise more than 70 members, including 13 human polyomaviruses (PyVs), all of which share a bidirectional genome organization mediated by the NCCR, which determines species and host cell specificity, persistence, replication, and virulence. Here, we demonstrate that the BKPyV NCCR is fine-tuned by an imperfect symmetry of core promoter elements centered around TATA and TATA-like sequences close to the EVGR and LVGR, respectively, which are governed by the directionality and affinity of two Sp1 sites. The data indicated that the BKPyV NCCR is poised toward EVGR expression, which can be readily unlatched by a simple switch affecting Sp1 binding. The resulting LTag, which is the major EVGR protein, drives viral genome replication, renders subsequent LVGR expression independently of archetypal promoter elements, and can overcome enhancer/promoter mutations and deletions. The data are pivotal for understanding how human PyV NCCRs mediate secondary host cell specificity, reactivation, and virulence in their natural hosts. The Polyomaviridae comprise more than 70 polyomavirus (PyV) members, including at least 13 human PyV (HPyV) species (1). HPyV seroprevalence data obtained using the major capsid prote...

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“…In the setting of allogeneic HSCT, hemorrhagic cystitis is the most common type of BKPyV-associated disease, whose incidence has been reported to be 12-24% (1,6,20,21). As our findings strongly suggest the possibility of nosocomial BKPyV infection, strict infection control measures for BKPyV should be implemented to prevent exogenous exposure if any patients develop hemorrhagic cystitis or BKPyV viruria in a hematology ward, especially an HSCT unit (19). In addition, not only hemorrhagic cystitis but also BK viruria or viremia without clinical manifestation has been reported to be related to a poorer rate of survival and/or to progressive renal dysfunction (4,20).…”

Section: Discussionmentioning

confidence: 63%

“…Therefore, the incidence of BKPyV-associated disease might have been underestimated, and thus the prevention and effective treatment of BKPyV infection or disease in allogeneic HSCT recipients could improve the transplant outcome. As our findings strongly suggest the possibility of nosocomial BKPyV infection, strict infection control measures for BKPyV should be implemented to prevent exogenous exposure if any patients develop hemorrhagic cystitis or BKPyV viruria in a hematology ward, especially an HSCT unit (19).…”

Section: Discussionmentioning

confidence: 80%

“…In the present study, nosocomial BKPyV infection resulting in an outbreak of hemorrhagic cystitis occurred primarily in an inpatient setting. The route of transmission could be from patient to patient or via healthcare workers, facilities, or toilet equipment (19). Further studies are necessary to elucidate the routes of transmission by detecting BKPyV in the hospital environment, and would greatly help to control the spread of infection.…”

Section: Discussionmentioning

confidence: 99%

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Nosocomial BK Polyomavirus Infection Causing Hemorrhagic Cystitis Among Patients With Hematological Malignancies After Hematopoietic Stem Cell Transplantation

Kato

Mori

Suzuki

et al. 2017

American Journal of Transplantation

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BK polyomavirus (BKPyV) is recognized as a pathogen that causes diseases such as hemorrhagic cystitis and nephritis after allogeneic hematopoietic stem cell transplantation (HSCT) or renal transplantation. BKPyV-associated disease is thought to occur through reactivation under immunosuppression. However, the possibility of its nosocomial transmission and the clinical significance of such transmission have not been elucidated. During a 6-month period, nine adult patients (median age: 47 years) who had hematological disorders and who were treated with HSCT (n = 7) or chemotherapy (n = 2) in a single hematology department developed hemorrhagic cystitis due to BKPyV infection. The polymerase chain reaction products of BKPyV DNA obtained from each patient were sequenced. Of the nine patients, six had subtype I, 2 had subtype IV, and 1 had subtype II or III. In the alignment of sequences, four and two of the six subtype I strains were completely homologous (100%). These results strongly suggest that BKPyV has the potential to cause nosocomial infection within a medical facility, especially among recipients of HSCT. Further studies are clearly warranted to elucidate the route(s) of BKPyV transmission in order to establish optimal infection control.

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Human Adenovirus, Polyomavirus, and Parvovirus Infections in Patients Undergoing Hematopoietic Stem Cell Transplantation

Cited by 13 publications

References 182 publications

The “ABC” of Virus-Specific T Cell Immunity in Solid Organ Transplantation

The “ABC” of Virus-Specific T Cell Immunity in Solid Organ Transplantation

Imperfect Symmetry of Sp1 and Core Promoter Sequences Regulates Early and Late Virus Gene Expression of the Bidirectional BK Polyomavirus Noncoding Control Region

Nosocomial BK Polyomavirus Infection Causing Hemorrhagic Cystitis Among Patients With Hematological Malignancies After Hematopoietic Stem Cell Transplantation

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