Polyomaviruses

Definition

Human polyomaviruses comprise at least 14 species, denoted human polyomavirus 1 to 14, and five of these are associated with human diseases ( Table 341-1 ). Of the types of polyomaviruses that infect humans, the principal causes of human disease are BK polyomavirus, JC polyomavirus, Merkel cell polyomavirus, human polyomavirus 7, and Trichodysplasia spinulosa polyomavirus.

Epidemiology

Seroprevalence studies of antibodies against the different human polyomavirus Vp1 capsid proteins indicate different exposure rates ranging from 10% for polyomavirus 9 to above 90% for BK polyomavirus (human polyomavirus 1) and human polyomavirus 10. Primary infections commonly occur independently from one another during childhood and adolescence, with smaller increases in seroconversion until the seventh decade of life. The route of transmission likely involves the respiratory, oropharyngeal, or gastrointestinal tract after direct contact or environmental exposure. There is little if any cross-neutralizing immunity against other human polyomavirus species. Ultimately, the average adult will be infected with 6 to 8 different human polyomaviruses.

Pathobiology

The early viral gene region encodes regulatory proteins called large and small tumor antigens that interfere with the functions of pRb-retinoblastoma and the p53-protein, override the cell’s control of division, and shift the host cells into S-phase to provide abundant enzymes and building blocks for efficient polyomavirus replication. The resulting hyperproliferative, transformed phenotype inactivates DNA-repair and apoptosis. Human polyomavirus-specific immunity relies upon neutralizing and opsonizing antibodies directed against receptor-binding and other domains on the viral capsid Vp1, thereby interfering with new rounds of infection and clearing circulating viral progeny and debris. Virus-specific CD4 helper and cytotoxic CD8 T cells aid in the clearance of virus-replicating cells. In immunocompetent individuals, these responses are sufficient to minimize local replication and to prevent polyomavirus diseases.

Clinical Manifestations and Diagnosis

No specific symptoms or signs have been linked to primary human polyomavirus infection in the general population, presumably because of subclinical or nonspecific manifestations. In immunocompromised patients, however, human polyomaviruses can cause major diseases of the renourinary tract, central nervous system, and skin.

Definition

In BK polyomavirus–associated nephropathy, the structure and function of nephrons is damaged by progressive viral replication, thereby resulting in denuded tubular basement membranes, interstitial inflammation, tubulitis, interstitial fibrosis, and tubular atrophy that cause progressive functional decline and end-stage renal failure.

Epidemiology

BK polyomavirus nephropathy almost exclusively affects recipients of kidney transplants and is rarely diagnosed in other immunocompromised populations despite similar or higher intensity of immunosuppression. Biopsy-proven disease develops in about 8% (range 1% to 15%) of patients in the first 2 years after kidney transplantation, but the true rates are higher because focal early-stage involvement, especially in the medulla, is missed by needle biopsy. Given the approximately 75,000 kidney transplants annually in North America and Europe, about 7500 kidney patients per year are at risk for premature renal allograft failure and return to dialysis.

BK polyomavirus–DNAemia levels correlate with onset, extent, and resolution of proven BK polyomavirus–associated nephropathy and then drop to undetectable levels with half-lives of less than 2 hours upon allograft nephrectomy. The risk of BK polyomavirus–DNAemia and nephropathy is higher with tacrolimus compared with cyclosporine immunosuppression, is lower for mTOR inhibitor combinations, and increases following treatment with high-dose corticosteroids for acute rejection ( Chapter 117 ).

Recipient risk factors include male gender, older age, and low or undetectable levels of BK polyomavirus–specific antibodies, as well as lack of certain human leukocyte antigen (HLA)-types such as B51, B7, B8, and A24. Donor risk factors include pretransplant urinary shedding of BK polyomavirus, exposure to a BK polyomavirus subtype to which the recipient does not have detectable antibodies, and an increasing number of HLA-mismatches.

Pathobiology

By transplanting the kidney, recipients are exposed to latent or replicating BK polyomavirus in the donor organ. Lack of sufficient BK polyomavirus–specific immunity leaves viral replication unchecked, with corresponding cytopathic changes of the renal tubular epithelial cells. Less frequently, the recipient’s own virus gains access to the renal allograft by reflux from the bladder. Lytic release of intranuclear virions permits cell-to-cell spread inside the tubules and to the downstream transitional and urothelial cells, thereby further amplifying viral replication and leading to average viruria of 100 million copies/mL. Increasing cytopathic damage and necrosis induce prominent interstitial inflammation and tubulitis, which are followed by irreversible interstitial fibrosis and tubular atrophy.

Clinical Manifestations

BK polyomavirus nephropathy is initially asymptomatic without affecting the function of the allograft. As damage to the allograft progresses, however, the serum creatinine concentration increases. High-level viruria develops in 20% to 40% of kidney transplant recipients, approximately 50% of whom develop BK polyomavirus–DNAemia after 0.5 to 2 months as a sign of viral replication in the allograft. Without effective interventions, increasing levels and durations of BK polyomavirus–DNAemia are associated with declining renal allograft function.

Diagnosis

Differentiating acute rejection from viral nephritis is important because the treatments (increasing or reducing immunosuppression) are the opposite of each other. In kidney transplant patients with declining renal function, a biopsy of the renal allograft is commonly indicated to search for T-cell-mediated or antibody-mediated rejection, drug toxicity, and BK polyomavirus nephropathy ( Chapter 117 ). The cytopathic and immunohistochemistry changes of BK polyomavirus nephropathy are characteristic ( E-Fig. 341-1 ). In unclear cases, other viral diseases presenting with intranuclear inclusions (e.g., adenovirus, herpes simplex, and cytomegalovirus) should be excluded.

In kidney transplant patients who present with baseline renal function and sustained or increasing BK polyomavirus–DNAemia, a biopsy is not indicated because allograft biopsy cannot exclude BK polyomavirus nephropathy. Criteria for a clinical diagnosis are: probable BK polyomavirus nephropathy, defined as sustained plasma BK polyomavirus loads of greater than 1000 copies/mL for more than 2 weeks, and presumptive BK polyomavirus nephropathy, defined as plasma BK polyomavirus loads above 10,000 copies/mL or the corresponding genome equivalent.

Treatment and Prevention

Prognosis

After reducing immunosuppression, plasma viral loads decline in 90% of kidney transplant patients within 6 to 12 months, but allograft rejection may occur in 10% of patients. Longer-term outcomes may be adversely affected by smoldering viral replication, T-cell- and/or antibody-mediated rejection, interstitial fibrosis, and tubular atrophy, all of which promote premature allograft failure within 10 years ( Chapter 117 ). Re-transplantation has been successful after several months of reduced or discontinued immunosuppression and clearance of BK polyomavirus-DNAemia, but recurrent disease may occur.