the residual HIV virus would simply die out about two to three years after patients began taking effective antiretroviral drugs, Greene says. Those drugs prevent the virus from converting new host cells into virus-producing factories. Without a host, viral particles can exist for only a short time in the blood plasma, he says.
But starting in 1995, researchers discovered the presence of the latently infected cells called resting memory CD4+ T cells, a long-lived and self-renewing cell population that is also more numerous than scientists had expected, Greene said in an October review article in the journal Cell. One researcher estimated that it would take 73 years of antiretroviral therapy to exhaust the latent HIV reservoir.
If patients go off their HIV medicines, some of the reservoir cells switch into active mode and begin cranking out virus particles, which then infect a new round of unprotected blood cells.
But researchers are now wondering: What if the reservoir cells could be forced to switch into active mode while patients were still taking their antiretroviral drugs? Would the latently infected cells then die—as most blood cells do when they’re forced to manufacture copies of the HIV virus? If so, the HIV reservoir might be exhausted without harming the patient. Greene and Gilead are both part of scientific consortia that are looking for drugs that can safely “shock” the reservoir cells into a reactivated state.
Gilead found such a drug, romidepsin (Istodax), by screening its own library of compounds, as well as all FDA-approved drugs. Romidepsin is a Celgene drug approved to treat a type of skin cancer, cutaneous T-cell lymphoma. But it can also activate cells latently infected with HIV.
Romidepsin will soon be used as a “test of concept” drug in a clinical trial sponsored by the National Institute of Allergy and Infectious Diseases (NIAID) and supported by Gilead, Celgene, and other partners, Geleziunas says. Investigators will dose HIV- positive participants with romidepsin while maintaining them on their antiretroviral medicines. Using a variety of different tests, the investigators will then measure how much of the HIV reservoir has been depleted.
Geleziunas doesn’t expect this trial to yield a treatment, but the procedures developed could one day validate a future therapy. Romidepsin isn’t the most powerful activator of latently infected cells—in lab studies, certain immune system stimulants are more potent. But romidepsin was chosen for the trial because it has a known safety profile as a drug already approved to treat human beings, Geleziunas says.
It’s possible that several rounds of activation over time will be required to induce all the latently infected cells to transform into a mode that makes them more vulnerable to cell death than they are in their resting state, Geleziunas says. A multiple dose study with romidepsin is being planned.
But if activation alone is not enough to kill all the latently infected cells, another agent will have to be added to finish them off, Greene says. He estimates that the reservoir contains about a million cells.
“You’ve got to get every one of them,” Greene says. This “shock and kill” tactic is being pursued by a research consortium Greene belongs to.
Again, any clinical trial of this tactic would be conducted with participants who continued taking their antiretroviral drugs. Trial investigators would be relying on these drugs to protect uninfected cells from the temporary surge of new HIV virus produced by the activation of latently infected cells.
Gilead already has a line on a drug that might play the “kill” role in a “shock and kill” regimen against the HIV cell reservoir, Geleziunas says. In preclinical research, the company has been studying the effects of an experimental immune modulation drug against viral infections. This agent helps mobilize two types of immune system cells that might destroy reactivated cells that have been harboring the HIV reservoir. The compound is believed to boost the action of a protein, toll-like receptor 7 or TLR7, which activates cytotoxic T-cells called CD8+ cells and NK or “natural killer” cells.
In further collaborations, Gilead is exploring two other possible HIV eradication strategies. The first draws on naturally occurring antibodies found in the blood of certain patients in Africa who have been called “elite neutralizers.” Their protective antibodies are called “broadly neutralizing” because they work against a wide range of viral strains.
Copies of these monoclonal antibodies could be part of a new treatment, Geleziunas says. “We could combine this with antiretroviral drugs and hopefully achieve sustained viral suppression,” Geleziunas says. If so, researchers could later try discontinuing the maintenance drugs, he says.
Gilead is also supporting studies of a vaccination method developed by Louis Picker at the Oregon Health & Science University. Picker’s technology appears to train the immune system to patrol continuously for certain pathogens in a long-term “seek and destroy” campaign that might some day be useful against the latent HIV reservoir.
In preclinical studies, Picker created a vaccine for SIV, a virus similar to HIV that infects monkeys. He joined SIV to a sort of vaccine vehicle or vector—a virus called cytomegalovirus that commonly infects humans and usually doesn’t cause disease. That vaccine, used as a preventive measure, protected half of a group of uninfected monkeys from SIV when they were exposed to the deadly simian immunodeficiency virus. Those monkeys produced virus, but their immune systems cleared it completely within three years.
“That is without precedent,” Geleziunas says. Picker’s group is trying to figure out why only half the monkeys benefited from the vaccine, and is also creating human cytomegalovirus vaccine vectors to carry the HIV virus for a potential vaccine for people. Picker co-founded a company, Portland, OR-based Tomegavax, to develop the technology.
Gilead is now participating in a collaboration with Picker, the Gates Foundation and other partners to figure out whether the SIV vaccine might be turned into a therapy or cure for monkeys already infected with SIV. In a study that has already begun, infected monkeys are treated with antiretroviral drugs, and then given the SIV-cytomegalovirus vaccine. After as much as a year, researchers will check to see whether the virus population rebounds when antiretroviral drugs are stopped. If the virus doesn’t return, the same method might be tried in clinical trials to see if a similar HIV vaccine could wipe out the HIV cell reservoir in humans.
Geleziunas says Gilead’s HIV eradication program includes a large group of well-supported scientists. They’ll explore any type of therapy that works best, whether it’s small molecules drugs, biologics, or vaccines, he says.
“We really don’t care where it comes from,” Geleziunas says. “We’ll go where the science takes us.”
