The first researchers who tried to stop the AIDS epidemic in the 1980s were faced with a terrifying virus that invaded key cells of the immune system, forced them to make many copies of itself, and burst the cells open in the process, leaving the human host defenseless against an onslaught of HIV and other infections.
Looking back on that drive to find the first HIV drugs, the task seems relatively simple to Romas Geleziunas—at least, compared to the problem he's tackling now.
Geleziunas, director of clinical virology at Foster City, CA-based Gilead Sciences is trying to thwart a second, more insidious way the HIV virus invades cells. Early in the course of infection, the virus inserts itself into the genome of immune system cells, but without either copying itself or killing the cell. The cell and the virus then wait together in a kind of slumber. But they can later awaken to unleash a new generation of infectious virus particles.
This reservoir of latently infected cells is now seen as the barrier standing in the way of a longed-for cure that could free HIV-positive individuals from a lifetime of taking the antiretroviral drugs developed by Gilead and other companies since the late 1980s. Those drugs protect uninfected cells, drive down blood levels of the virus, and stave off full-blown AIDS. But they don't eliminate the HIV reservoir, which appears to be complex and pretty mysterious.
"We don't fully understand what are the reservoirs that harbor HIV," Geleziunas says. "That makes the mission very, very tough."
Gilead, the world's largest maker of antiretroviral drugs, began its search for ways to eradicate the HIV virus from the body about five years ago, Geleziunas says. He's ready for the natural question that follows: Why would Gilead push hard to eliminate the need for its own HIV drugs, which bring in about $9 billion in annual revenue, and which can change a deadly disease into a chronic condition managed by a single daily pill?
Geleziunas says the answer is simple: the company knows that patients would rather be released from the need for any HIV medicines. Gilead is on the hunt for next-generation HIV therapies it can commercialize that would wipe out the virus—hopefully for good—after a limited time on treatment. "We were one of the first companies into the field," he says.
The company doesn't use the freighted word "cure" to describe its goal. "We prefer to say we want to create a state of HIV remission that could be controlled without drugs," Geleziunas says.
Gilead has been exploring a range of different strategies to block the HIV virus from surging back after treatment, and has been lining up research partnerships that include other drug developers, academic researchers, and government agencies.
"We've created a hub for clinical and basic research," he says.
Gilead's efforts are part of a larger research mobilization that has been galvanized by recent reports about a few HIV-positive patients who have actually been able to stop their drug regimens—though they did this after treatments that might be difficult to extend to large numbers of patients. For example, the HIV-positive "Berlin patient," whose case was reported in March 2011 in the scientific journal Blood by a research team at Charite´-University Medicine Berlin, in Berlin Germany, received a bone marrow transplant for his leukemia from a donor who happened to be one of the rare individuals with a natural genetic immunity to HIV.
Even so, scientists pursuing a "functional cure" for HIV have been emboldened by the Berlin patient and other cases, says Dr. Warner Greene, director of the Gladstone Institute of Virology and Immunology in San Francisco.
"The anecdotal cases suggest that we're not tilting at windmills," says Greene, a top HIV expert.
Greene sees an urgent need for a cure. Patients taking long-term antiretroviral drug regimens are still vulnerable to the premature onset of diseases of aging. Across the globe, about 35 million people are infected with HIV. (About the same number have died.) The cost of maintaining patients on lifetime therapy is a significant burden even for developed countries, while the drugs are inaccessible to millions of infected people in Africa and other regions, Greene says.
"Sixteen million people are not receiving it, and they're dying," he says.
Greene points to gene therapy as one of the major strategies being pursued to achieve a functional cure. Richmond, CA-based Sangamo Biosciences recently showed progress in its drive to modify the genes of HIV- positive patients and replicate the immunity that the "Berlin patient" acquired from his bone marrow donor.
Greene says he values Sangamo's work, but he expects that most of the world's HIV-positive population won't be able to pay for Sangamo's multi-step procedure to modify the genes in blood cells of individual patients. To achieve global eradication of HIV, researchers will have to develop simpler treatments that can be scaled up for mass populations, Greene says.
That may mean devising a drug, or drug combination, that depletes the HIV reservoir in latently infected cells. And the task doesn't look easy so far, Greene says.
"It's a bigger, nastier problem than we thought," he says.
Scientists had optimistically predicted in the mid-1990s that 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."
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