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 (NASDAQ: SGMO) 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
