BK virus

BK virus (BKPyV) is a small non-enveloped DNA virus carried silently for life by the great majority of people and, in the healthy host, entirely harmless. Its importance is confined almost exclusively to transplantation, where the immunosuppression needed to protect the graft releases the virus to replicate and cause disease. In kidney transplant recipients it causes BK-virus-associated nephropathy, a destructive infection of the transplanted kidney that is now a leading infectious cause of graft failure. In recipients of an allogeneic haematopoietic stem cell transplant it causes haemorrhagic cystitis, a painful bleeding inflammation of the bladder. The virus is acquired without symptoms in childhood and persists in the kidney and urinary tract, reactivating only when cellular immunity is suppressed; in the transplanted kidney the replicating virus is often carried in with the donor organ. There is no vaccine and no antiviral of proven benefit, so management turns on detecting reactivation early through the blood viral load and carefully reducing immunosuppression to let the immune system regain control. Its close relative JC virus shares the same lifelong urinary-tract persistence but, because it uses a different receptor, targets the brain instead.

Discovery and historical significance

BK virus was isolated in 1971 by Gardner and colleagues from the urine of a renal transplant recipient, and named, like JC virus, from that patient’s initials. The two viruses were discovered in the same year and have been studied as a pair ever since, the first two human polyomaviruses and for four decades the only ones firmly linked to human disease. For two decades BK virus remained largely a laboratory curiosity, detectable in urine but rarely associated with overt illness. That changed in the 1990s, when more potent immunosuppressive regimens, in particular the combination of tacrolimus and mycophenolate, came into wide use in kidney transplantation and BK-virus-associated nephropathy emerged as a significant and previously unrecognised cause of graft loss. Recognition that the disease could be intercepted by monitoring the virus in blood and urine, rather than waiting for the kidney to fail, has shaped its management since.

Classification, structure, and genome

Classification

BK virus belongs to the family Polyomaviridae, genus Betapolyomavirus, with the current International Committee on Taxonomy of Viruses species name Betapolyomavirus hominis (formerly Human polyomavirus 1). It sits alongside its close relatives JC virus (Betapolyomavirus secuhominis) and the simian virus SV40, sharing about 75 per cent genome identity with JC virus. Four major genotypes (subgroups) are recognised, of which genotype I is the most common worldwide. The prototype Gardner strain carries a rearranged control region associated with efficient replication.

Virion structure

The virion is a non-enveloped icosahedral particle about 40 to 45 nanometres in diameter, built on the polyomavirus plan of 72 pentamers of the major capsid protein VP1 arranged on a triangulation number T equals 7 lattice, each pentamer holding a single internal molecule of VP2 or VP3. Only VP1 is surface-exposed and it carries the receptor-binding site and the determinants recognised by neutralising antibody. Calcium ions and inter-pentamer disulfide bonds stabilise the capsid, and the genome is packaged inside as a minichromosome wound on host histones. The particle is robust and, importantly for the urinary tract, stable in urine, where it can be shed at very high titre.

Genome organisation

The genome is a single circular molecule of double-stranded DNA of about 5,000 base pairs in three parts: an early region encoding the large T and small t antigens, a late region encoding the capsid proteins VP1, VP2 and VP3 together with the agnoprotein, and between them the non-coding control region (NCCR), which holds the origin of replication and a bidirectional promoter. As in JC virus, the control region exists as a stable archetype in the urine of healthy carriers and, on reactivation under immunosuppression, acquires deletions and duplications. The rearranged control region strongly upregulates early-gene transcription, driving the higher viral loads and tissue damage of active disease.

Replication cycle

BK virus follows the canonical polyomavirus replication arc, but it diverges from JC virus at the very first step, and that divergence dictates its disease. The two viruses are about 75 per cent identical and run essentially the same intranuclear cycle, yet they attach to different receptors and enter cells by different routes, which sends them to different tissues.

BK virus attaches to branched gangliosides bearing terminal sialic acid, chiefly GT1b and GD1b, which are displayed on renal tubular epithelial cells and urothelium, and it enters by caveolin-dependent endocytosis. (JC virus, by contrast, uses a linear sialylated glycan with the serotonin 5-HT2A receptor and a clathrin-dependent route into glial cells.) The virion is trafficked through the endoplasmic reticulum, where the rigid capsid is partially disassembled, and the genome is delivered to the nucleus. There the cycle is the polyomavirus standard: host RNA polymerase II transcribes the early genes, and large T antigen drives the resting cell into S phase by binding and inactivating the retinoblastoma family and p53, making available the host replication machinery the virus lacks. Large T antigen then binds the SV40-like origin and initiates bidirectional replication of the episome; the late genes follow, the capsid proteins assemble progeny virions in the nucleus, and because the virus is non-enveloped, release is by lysis of the host cell. That lytic release is the direct cause of the tissue damage seen in disease, the sloughing and necrosis of infected tubular cells in the kidney.

The persistence that follows primary infection is not a silent latency but a low-level chronic infection of the kidney and urothelium held in check by T-cell immunity. Reactivation, control-region rearrangement and high-level replication occur together only when immunosuppression removes that control.

Pathogenesis

BK virus is carried harmlessly by most people, and its pathology is essentially a disease of the transplant ward. Two pictures dominate, each the result of uncontrolled lytic replication in a different part of the urinary tract.

In the kidney transplant, BK-virus-associated nephropathy (BKVAN, also called polyomavirus-associated nephropathy) is uncontrolled replication in renal tubular epithelial cells. Infected cells enlarge, develop ground-glass intranuclear inclusions, round up and slough into the urine as “decoy cells”, and lyse, releasing virus and provoking an interstitial inflammatory infiltrate. The process is graded histologically through three stages: an early cytopathic stage with little inflammation, an intermediate stage with interstitial inflammation and tubulitis, and a late stage of tubular atrophy and interstitial fibrosis that represents irreversible scarring. A central difficulty is that the inflammatory stage closely resembles acute cellular rejection, yet the two demand opposite changes in immunosuppression. In the kidney transplant the replicating virus is frequently donor-derived, carried in with the graft, and a seronegative recipient of a seropositive donor kidney is at higher risk.

In the allogeneic stem cell transplant recipient, BK virus replicates in the urothelium to cause haemorrhagic cystitis, with denudation and bleeding of the bladder lining. This is amplified by two transplant-specific factors: prior urotoxic conditioning (cyclophosphamide and its metabolite acrolein) that damages the bladder epithelium, and the inflammatory surge of immune reconstitution at engraftment. Control of BK virus depends on cellular immunity, in particular BK-virus-specific CD8 cytotoxic T cells, with neutralising antibody contributing; recovery of the T-cell response accompanies clearance. After very prolonged replication, BK virus is rarely implicated in a polyomavirus-associated urothelial carcinoma, in which the large T antigen is expressed and an APOBEC mutational signature is found.

Epidemiology

BK virus is distributed worldwide and infects almost everyone: seroprevalence exceeds 80 to 90 per cent of adults, with primary infection in early childhood, probably by a respiratory or oral route, usually unaccompanied by recognised illness. Asymptomatic urinary reactivation is common in the general population, for example in pregnancy, without consequence.

Clinically significant disease, by contrast, is concentrated in two transplant populations. Among kidney transplant recipients, high-level urinary shedding appears in a large minority and detectable virus in the blood in roughly one in five within the first year, with biopsy-proven BKVAN affecting on the order of 1 to 15 per cent. Among allogeneic haematopoietic stem cell transplant recipients, haemorrhagic cystitis complicates a substantial fraction, with reported ranges from about 5 to as high as 50 per cent depending on definition and conditioning. BKVAN is overwhelmingly a disease of the transplanted kidney and is rare in other solid organ transplants despite comparable immunosuppression, a reminder that the kidney is both the reservoir and the target.

Natural history

The natural history mirrors that of JC virus but plays out in the urinary tract. Primary infection in childhood is silent, and the virus then persists for life in the kidney and urothelium, shed intermittently in the urine of healthy people. In the immunocompetent host nothing further happens. After kidney transplantation the sequence is more orderly and can be tracked: immunosuppression permits high-level replication, which appears first as high-level urinary shedding, then as detectable BK virus in the blood, and finally, if unchecked, as nephropathy. This cascade unfolds mostly within the first year, when immunosuppression is heaviest, although a meaningful minority of nephropathy presents later. It is precisely because the progression is stepwise and detectable in blood before the kidney is damaged that screening and pre-emptive intervention are effective.

Clinical presentations and complications

The clinical spectrum is dominated by the two transplant syndromes, summarised below, with two rarer complications.

Disease	Setting	Affected tissue	Presentation
BK-virus-associated nephropathy	Kidney transplant	Renal tubular epithelium	Rising creatinine, graft dysfunction; often asymptomatic, found on screening
Haemorrhagic cystitis	Allogeneic stem cell transplant	Urothelium	Dysuria, frequency, visible haematuria with clots

BK-virus-associated nephropathy is typically silent and detected through screening or as an unexplained rise in serum creatinine, rather than through symptoms; left unrecognised it progresses to graft failure, and the risk of returning to dialysis rises steeply with histological stage. Haemorrhagic cystitis, by contrast, is symptomatic and often distressing, of late onset some 2 to 12 weeks after engraftment, defined by the combination of cystitis symptoms, visible haematuria and high-level BK viruria, and distinct from the early, brief haemorrhagic cystitis caused by conditioning toxicity in the first days after transplant. Two further complications are ureteric stenosis, a fibrosing narrowing of the ureter that can obstruct the graft, and, rarely and only after prolonged replication, a polyomavirus-associated urothelial carcinoma.

Diagnosis

Diagnosis is built on quantitative BK virus DNA testing, with the plasma viral load as the pivotal measurement. BK virus in the blood reflects significant renal replication and is the marker used both to screen and to decide on treatment; urinary shedding is near-universal in reactivation and is more sensitive but far less specific, so a high urine load alone does not establish nephropathy. Urine cytology can show decoy cells (tubular and urothelial cells with ground-glass intranuclear inclusions), and urinary aggregates of virions known as Haufen correlate with established nephropathy.

The diagnostic categories used in kidney transplantation are defined by the plasma load and by biopsy:

Category	Plasma BK virus DNA	Treat
Possible nephropathy	High urinary shedding, plasma negative	No
Probable nephropathy	Above 1,000 copies per millilitre, sustained	Usually
Presumptive nephropathy	Above 10,000 copies per millilitre	Yes
Proven nephropathy	Biopsy-confirmed (see below)	Yes

Proven nephropathy requires a renal biopsy showing viral cytopathic change with an inflammatory infiltrate and confirmation by SV40 large T antigen immunohistochemistry, which uses a cross-reacting antibody to stain infected tubular nuclei. Because the infection is focal and favours the medulla, at least two cores including medulla are recommended, and a negative stain does not exclude early or patchy disease. Biopsy is not required to begin treatment in a patient with a stable baseline kidney and a diagnostic plasma load; it is reserved for cases where coexisting rejection or impaired baseline function complicates the decision.

Management

There is no antiviral of proven benefit against BK virus, and the mainstay of treatment is to restore BK-virus-specific cellular immunity by stepwise reduction of immunosuppression, guided by the plasma viral load. Typical targets are a lower calcineurin-inhibitor exposure (for example a tacrolimus trough below 6 nanograms per millilitre, or ciclosporin below 150) and reduction of the antimetabolite to no more than half its maintenance dose. Reducing the antimetabolite first or the calcineurin inhibitor first are regarded as broadly equivalent. Done promptly, this clears the virus from the blood in around 80 per cent of patients. The one important exception is concurrent biopsy-proven acute rejection, which inverts the logic: rejection is treated first and immunosuppression reduced only afterwards, because the two conditions pull in opposite directions.

Adjunctive drugs are used only when reduction of immunosuppression fails, and the evidence for all of them is weak. Cidofovir gives inconsistent results and carries nephrotoxicity and uveitis; brincidofovir remains investigational; leflunomide lacks controlled support and is toxic; intravenous immunoglobulin contains neutralising antibody and is used empirically, always alongside other measures. Fluoroquinolones are explicitly not recommended, a randomised trial of levofloxacin having shown no effect on viral load. Re-transplantation after graft loss from nephropathy is feasible once the blood viral load has cleared, with good medium-term graft survival under frequent screening. Haemorrhagic cystitis in the stem cell transplant recipient is managed supportively, with hydration, bladder irrigation, clot evacuation and transfusion as needed, while immune recovery brings the infection under control; reducing immunosuppression is harder here because of the risk of graft-versus-host disease.

Prevention and public health

Because BK virus is acquired universally in childhood and carried for life, there is no prospect of preventing infection, and prevention instead means preventing nephropathy in the kidney transplant recipient by catching reactivation before it damages the graft. Current guidance is to screen all kidney transplant recipients for BK virus in the plasma at intervals, conventionally monthly until about nine months after transplant and then every three months until two years, and to reduce immunosuppression pre-emptively when the viral load rises into the treatable range. This blood-load-guided, pre-emptive approach is the central preventive strategy and the analogue of the antibody-index and imaging surveillance used for JC virus.

Vaccination

There is no vaccine against BK virus and none in routine prospect. As with JC virus, almost everyone is already infected, so a useful vaccine would have to strengthen the cellular immunity that controls reactivation in transplant recipients rather than prevent acquisition, and that is a difficult target in the very patients who are deliberately immunosuppressed. Prevention therefore continues to rest on surveillance and the careful titration of immunosuppression rather than immunisation.

South African context

BK virus is relevant in South Africa wherever kidney transplantation and allogeneic stem cell transplantation are practised, which is concentrated in the larger public and private transplant centres. The constraint is access to quantitative BK virus PCR: plasma viral-load testing, the basis of the screening and pre-emptive-reduction strategy, is available mainly through tertiary and academic laboratories, so the intensive screening schedules recommended in international guidance can be difficult to deliver uniformly across the programme. BK-virus-associated nephropathy is not a notifiable condition, and there is no dedicated national surveillance for it; recognition depends on transplant units maintaining their own monitoring. The management principle, reducing immunosuppression under viral-load guidance while watching for rejection, is the same as elsewhere and does not depend on drugs that are unavailable locally.

References and recommended reading

• DeCaprio JA, Imperiale MJ, Hirsch HH. Polyomaviridae. In: Howley PM, Knipe DM, Damania BA, Cohen JI, eds. Fields Virology: DNA Viruses. 7th ed. Wolters Kluwer; 2022:1-44. The primary reference for the molecular virology, the replication cycle, persistence, and the BKPyV-associated diseases.
• Greenlee JE, Hirsch HH. Polyomaviruses. In: Richman DD, Whitley RJ, Hayden FG (eds.), Clinical Virology, 4th edition. ASM Press; 2016. The clinical account of BK-virus nephropathy and haemorrhagic cystitis, diagnosis and management.
• Hirsch HH, Randhawa PS, on behalf of the AST Infectious Diseases Community of Practice. BK polyomavirus in solid organ transplantation: guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clinical Transplantation. 2019;33:e13528. The current source for screening, the diagnostic categories and the management of BK-virus-associated nephropathy.
• Fenner and White’s Medical Virology, 5th edition. Academic Press; 2017, Chapter 20 (Polyomaviruses). Concise overview of the family and the human polyomaviruses.