By the end of the year, Montaner will begin recruiting participants for a highly anticipated trial aimed at reducing that reservoir with interferon, a protein made by our bodies that boosts the immune system.
Wistar will spearhead the 54-person trial with a $7 million grant from the National Institutes of Health. Researchers hope to confirm data from a 2011 Wistar trial that suggested interferon could diminish the reservoir and do what antiretrovirals have for decades been unable to accomplish: take a person from "undetectable" to "cured."
In the 2011 trial, also led by Montaner, 20 undetectable patients took interferon alongside antiretroviral drugs for five weeks, then stopped taking the drugs but continued receiving interferon injections, some for an additional 24 weeks.
Received wisdom said that when the antiretroviral drugs were stopped, the virus would begin replicating within weeks. But in 9 patients, that didn't happen. They suppressed the virus for months, remaining undetectable on interferon alone. It was the first clinical evidence that HIV could be suppressed without the drugs, says Montaner, who led that study.
Something else unexpected happened. Seven of the 9 patients' blood was later available to sample, and measurements suggested that all 7 had less HIV in their system without antiretroviral drugs than at the outset of the trial, when they were still taking the drugs. It appeared their viral reservoirs hadn't merely remained suppressed solely on interferon - they had shrunk.
"Really, really provocative data was generated by that trial," says Satish Pillai, an associate professor at the University of California San Francisco who does HIV-related interferon research. "But it was just too small and not systematic enough. A lot of people are not convinced yet that the interferon has a legitimate effect against the reservoir," says Pillai, who was not involved in the Wistar study. " 'This is interesting, but not enough for me to drink the Kool-Aid.' That's the response I've gotten from most people."
The forthcoming trial, larger and with a more sophisticated study design than the one in 2011, "is going to be very closely watched" by HIV researchers worldwide, he says.
There's "a tremendous amount of interest" in interferon among HIV researchers, Pillai says. "If it's successful, there will be a lot of people who want to investigate how interferon did what it did. But if this trial shows that interferon doesn't really do anything to the reservoir, it will probably stifle interest." For now, though, there's no doubt: "Interferon is extremely hot."
The same could have been said in the 1980s, when synthetic interferon was first manufactured on a commercial scale. It was called a "wonder drug" that might treat everything from cancer to the common cold. And for some diseases, such as hepatitis C, which interferon can help cure, it's been quite useful, though it often causes nasty flulike side effects.
But when it was tested as a possible HIV treatment early in the AIDS crisis, it showed little promise, and was shelved in favor of antiretroviral drugs, which are highly effective in suppressing HIV and remain the treatment of choice today.
So if interferon didn't work then, why try it decades later?
Wistar's Montaner has a theory.
In the 1980s, interferon was given to HIV patients whose immune systems were severely impaired, as they hadn't yet received antiretroviral drugs, he says. What if you gave interferon to patients after their immune systems were stabilized with those drugs?
His new study, which could take three years to complete, aims to answer that question and determine if interferon can penetrate and reduce the viral reservoir.
If it can, and the trial sheds more light on how that happens, "then we would be pretty confident that we're taking a very solid step towards eradication," Montaner says.
People who want to participate in the trial should contact Ken Lynn at the University of Pennsylvania at 215-662-8217 or firstname.lastname@example.org