Scientists at Fred Hutchinson Cancer Research Center in Seattle have strengthened the case that HIV, the virus that causes AIDS, may take a page from cancer’s playbook.
The research led by Drs. Joshua Schiffer and Daniel Reeves has significant implications for strategies to cleanse remaining reservoirs of HIV infection, which, if ever achieved, would amount to a functional cure for HIV.
Their study, released online Friday in Nature Communications, lends strong support to one side of a debate about why HIV persists in patients who otherwise suppress the virus through lifelong treatment with antiviral drugs.
That debate centers on this: Does HIV survive in these patients through replication, in small pockets of infected cells that escape the drugs and continually copy the virus? Or is it through proliferation, the routine duplication of blood cells that have HIV genes from an earlier infection stitched into their own DNA? Proliferating cells harboring such genes can produce active infection if a patient stops taking the daily antiviral medications that keep HIV from spreading to healthy cells.
The Fred Hutch study points strongly in one direction: “We think that nearly all of these cells carrying HIV — greater than 99.9 percent — were generated via proliferation,” said Schiffer, a physician and researcher in the Hutch's Vaccine and Infectious Diseases Division who also uses computers to model HIV-eradication strategies.
This is important news for researchers worldwide who are trying to figure out how to stop HIV for good. Instead of trying to pick off hidden pockets of replicating virus, the study suggests it might be better to look for therapies that reduce cell proliferation, which is a standard strategy for blocking cancers.
Proliferation is the natural multiplication of genetically identical cells via cell division. In cancer, genetic changes tip this process into overdrive, and the mutated cells divide uncontrollably. Many cancer therapies rely on eliminating the population of proliferating, mutated cells. If that same strategy can stop immune-system cells — specifically white blood cells known as CD4 T cells — carrying HIV genes, it raises the prospect that these free-floating reservoirs of dangerous cells could be wiped out.
“We generated this idea — that HIV survives through proliferation of T cells — because we hang out here at Fred Hutch with immunologists,” Schiffer said. “Immunologists know that T cells proliferate, naturally turning over on a timescale of a couple months, upwards to a year.”
The latest findings lend urgency to a small clinical trial launched one year ago by Schiffer to test whether an anti-proliferative drug commonly used in transplant recipients might shrink or even eliminate HIV reservoirs in participants who are also taking antiviral drugs. “We jumped the gun on this. We have a clinical trial up and running based on this principle,” he said. The trial was made possible by a $200,000 grant from amfAR, the Foundation for AIDS Research.
The HIV-positive volunteers are taking mycophenolate mofetil, or MMF, a relatively inexpensive, readily available drug that suppresses multiplication of immune cells. It is already licensed to treat patients with rheumatic diseases, to suppress the immune system in solid organ transplant recipients, and to prevent graft-vs.-host disease after blood stem cell transplants.
The idea is that slowing the natural turnover of T cells that are carrying HIV in their genome would cause them to eventually die out, replaced by new generations of immune cells without HIV genes. The drug would also slow the proliferation of healthy T cells, but this is essentially a numbers game: The math works in favor of the uninfected. Prior mathematical studies suggest that this strategy could clear out all HIV infected cells within two to 10 years.
In this first trial, MMF is being tested on just five volunteers who have their HIV under control using antiviral therapy. Schiffer said early results of that trial are likely within a few months. The study will use extremely sensitive tests to track any declines in CD4 cells carrying HIV genes. The patients will not be taken off the antiviral drugs that stop active HIV from infecting cells.
At the heart of the newly published study is a mathematical analysis of telltale genetic signatures of HIV genes found in patients’ T cells. These signatures, Schiffer explains, reveal “where these viruses were born.” They each display something akin to the mailing addresses of their points of origin.
Such clues allow the scientists to infer whether the viruses sprang from scattered, ongoing viral replication or whether they arose from colonies of proliferating cells. Lots of different mailing addresses would signal replication; clusters of similar addresses favor proliferation. The study shows those postmarks of proliferation.
One of the statistical challenges facing these scientists is that HIV-positive T cells are exceedingly rare — perhaps one in a million CD4 cells carry the HIV genes inside them. That leads to a dearth of data that can make any conclusions difficult to reach.
Paper co-author Reeves, a research associate in Schiffer's group, solved that problem using statistical methods developed by wildlife biologists to account for populations of elusive animals — like foxes, wolves and eagles — based on a small number of observations in a large forest.
“It was a cool foray into reading a bunch of ecology papers and learning their methods,” Reeves said. “That was the motivation for doing this kind of analysis.”
The result is a mathematical model that strongly points to proliferation as the reason why HIV persists in patients who consistently take antiviral drugs. Schiffer stressed that this model cannot rule out the existence of hidden pockets of infected cells that are somehow shielded from antiviral drugs. But the study strengthens the theoretical underpinnings for a new strategy of rooting out HIV.
Sabin Russell is a former staff writer at Fred Hutchinson Cancer Center. For two decades he covered medical science, global health and health care economics for the San Francisco Chronicle, and he wrote extensively about infectious diseases, including HIV/AIDS. He was a Knight Science Journalism Fellow at MIT and a freelance writer for the New York Times and Health Affairs.
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