Polyomaviruses

Question 1

BK virus structure & classification

Answer 1

Family: Polyomaviridae
Genus: Polyomavirus

dsDNA supercoiled NON eneveloped

Baltimore: I

Question 2

BK clinical features

Answer 2

1. BKV allograft nephropathy - allograft failure
2. Haemorrhagic cystitis
3. GVHD in HSCT

Question 3

BK diagnostics

Answer 3

Urine RT-PCR - >10^9 indicative of haemorrhagic cystitis risk

Blood RT-PCR

HPE - Decoy cells
IHC - SV40 staining

Urine Cytology - Decoy cells

Question 4

BK treatment

Answer 4

1. Reducing MMF/Tac

No approved antiviral

2. Cidofivir - in vitro activity - BK does not encode for DNA polymerase (as CMV does) - so cidofovir may be damaging replicating host cells - so lower dose 0.25mg (1/10th dose for CMV) is enough
3. Leflunomide
4. IVIG
5. Vidarabine - nucleoside analog and therefore has to be phosphorylated to be active. This is a three-step process in which vidarabine is sequentially phosphorylated by kinases to the triphosphate ara-ATP. When used as a substrate for viral DNA polymerase, ara-ATP competitively inhibits dATP leading to the formation of ‘faulty’ DNA.

Question 5

Human polyomaviruses

Answer 5

1. BK
2. JC
3. Merkel cell polyomavirus is the cause of Merkel cell carcinoma
4. Trichodysplasia spinulosa polyomavirus is associated with trichodysplasia spinulosa, characterized by the development of cutaneous keratin “spines” and follicular papules most commonly on the face

Question 6

JC virus structure & classification

Answer 6

Family: Polyyonaviridae
Genus: Polyomavirus

dsDNA NON enveloped

Baltimore: I

Question 7

JC virus clinical manifestations

Answer 7

progressive multifocal leukoencephalopathy (PML), a demyelinating disorder that almost always occurs in the setting of immunocompromise, and presents with progressive focal neurologic deficits including ataxia, hemiparesis, visual field deficits, and cognitive impairment. PML has been reported most commonly in patients with advanced HIV (particularly before the availability of potent antiretroviral therapy), but it has also been reported in patients with hematologic malignancies and in patients receiving certain lymphocyte-targeted agents, such as NATALIZUMAB.

JCV cerebellar granule cell neuronopathy — JCV may cause a productive and lytic infection of cerebellar granule cell neurons, leading to ataxia, incoordination, dysarthria, and cerebellar atrophy [83-85]. This syndrome is named JCV granule cell neuronopathy (GCN). It causes cerebellar atrophy but does not result in white matter lesions of cerebellar PML. In some cases, JCV GCN may be the first manifestation of AIDS in HIV infection

Question 8

Trichodysplasia spinulosa

Answer 8

Trichodysplasia spinulosa (TS) polyomavirus (TSPyV) has been detected in lesions of TS, a rare skin disease in immunocompromised patients characterized by viral replication within keratinocytes and hyperproliferation of the inner root sheath cell. The diagnosis is characterized by the development of keratin spines (“spicules”) and follicular papules that often involve the face and is confirmed by a skin biopsy with characteristic histology or detection of the polyomavirus (SV-40 immunostaining, electron microscopy visualization of 40 to 45 nm viral particles in cells of the inner root sheath or molecular methods)

In addition to improving immune function (eg, by reducing immunosuppression), case reports have described improvement following topical cidofovir, valganciclovir, leflunomide, retinoids, or physical extraction of keratin spicules but controlled trials are lacking.

Question 9

PML diagnostics

Answer 9

MR brain

CSF JC PCR - even if PCR negative, if MR suggestive of PML, consider as possible PML

Question 10

JC/PML treatment

Answer 10

HIV - ART - but beware of IRIS in which case steroids are warranted

Non-HIV:

●Checkpoint inhibitors – The immune checkpoint inhibitors nivolumab and pembrolizumab are monoclonal antibodies that target programmed cell death protein 1 (PD-1), an inhibitory T-cell surface receptor that promotes self-tolerance and is a marker of immune exhaustion. Upon binding with its ligand, PD-1 inhibits T-cell proliferation and cytokine production. Pembrolizumab and nivolumab block this inhibitory reaction and have been used to reinvigorate antitumoral T-cell activity.

• Cidofovir - unclear benefit and data packing
• Viral specific T cells

Question 11

PML mortality

Answer 11

40% @ median 2 months

Question 12

Polyoma viruses subfamilies

Answer 12

Alpha polyoma: merkel cell and TDS

Beta polyoma is BK, JC, Ki, Wu

Ki&Wu - possible respiratory illness