When a benign bug turns troublesome
It’s one of the miracles of modern medicine: transplanting a functional kidney into someone whose own kidneys are failing. Once a feat worthy of a Nobel Prize, the operation is so common today it hardly raises an eyebrow. More than 15,000 are performed every year in the United States, and success rates have risen dramatically since the late 1970s, when powerful anti-rejection drugs first came on the scene.
And yet, a lowly virus—a naked assemblage of protein and DNA that doesn’t even own equipment to reproduce itself and has to borrow the machinery from cells it infects—can be the undoing of an otherwise successful transplant.
Michael Imperiale would like to be the undoing of that virus.
The virus, known as BKV, inhabits nearly all of us, usually living quite docilely. “Almost everyone gets infected in early childhood,” says Imperiale. Once BKV enters the body—perhaps through the respiratory system, although the exact route isn’t known—it travels down to the urinary tract where it remains throughout our lifetimes without causing any signs of illness in the vast majority of us.
But in transplant recipients—especially those who’ve received kidneys—BKV turns nasty, precipitating a life-threatening illness called polyomavirus nephropathy (PVN).
There are no effective drugs against the virus BKV, so the usual approach to treating PVN is to boost the patient’s own germ-fighting ability by cutting back on the immune-suppressing drugs that typically are used to prevent organ rejection.
“But when you do that, you increase the risk of rejection,” says Imperiale. Indeed, PVN leads to organ dysfunction in up to 10 percent of all kidney transplant patients, and the bug BKV is responsible for most cases of PVN. With PVN on the rise, finding ways to thwart the main culprit is a major priority for the transplant community.
Imperiale’s mission: Exploring BKV’s lifestyle and finding drugs that undermine its disease-causing tendencies without harming its human hosts. That’s not an easy task with a bug that depends so heavily on its host’s cellular apparatus to reproduce; therapies aimed at blocking the host enzymes that BKV borrows to reproduce could be as harmful to the host as to the virus.
“That’s why we need to know more about the interaction between the virus and the host cell, to see if there are parts of the process that we can safely target,” says Imperiale. To that end, his research group is studying BKV in lab-grown kidney cells. Thanks to a kidney cell culture system developed by David Humes, M.D., in the Department of Internal Medicine, these cells act just like kidney cells inside the body.
“In these cells, the virus replicates like crazy,” Imperiale says. In recent research, his lab group was able to shut it down with interferon gamma, a naturally occurring substance that is used as an antiviral and anticancer drug, and now they’re looking more closely to figure out exactly how the drug does the trick.
Getting the upper hand over BKV could ultimately be useful, not only in transplant medicine, but also in cancer treatment. Although the bug hasn’t been definitively implicated, early evidence suggests that it’s somehow involved in prostate cancer.
“If you ask me, ‘Does BKV cause prostate cancer?’ I’d have to say we don’t really know,” Imperiale says. "But it’s becoming increasingly clear that it has the means to do it, and we have some evidence that it might.”
Nailing down that connection, hinted at in preliminary studies, could pave the way to an anti-cancer vaccine like the one currently used to prevent cervical cancer, as well as pointing to treatments for existing cases of cancer.
