New thinking about HIV eradication
by Liz Highleyman
Now that effective combination antiretroviral therapy has restored health and extended lives for many people with HIV, researchers and advocates are again turning their attention to a cure.
On February 4, the AIDS Policy Project, in conjunction with Project Inform, held its first scientific update on HIV eradication, bringing together local experts to provide an overview of an exclusive conference held this past December on the Caribbean island of St. Martin.
"Current drugs are not a panacea," said Matt Sharp, Project Inform's director of treatment and prevention advocacy, who has survived on them for two decades. "Antiretroviral therapy has made HIV a chronic manageable disease, but it's still not a cure."
While treatment has dramatically reduced illness and death from opportunistic infections due to immune system collapse, a growing body of evidence shows that even low-level HIV replication can wreak havoc throughout the body, perhaps by triggering chronic inflammation. This may explain higher rates of non-AIDS problems such as heart and liver disease in HIV-positive people, as well as what looks like accelerated aging.
Today's potent regimens can knock HIV in the blood down to an "undetectable" level in most people who achieve good adherence, but ultra-sensitive tests reveal that a small amount remains behind.
HIV inserts its genetic material into the DNA of latent or inactive T-cells, and there it remains until the cell is activated. Today's drugs can fight virus in the blood, but not sequestered in latent cells. The trick, therefore, is to "wake up" these reservoir cells, causing them to release virus and making them visible to the immune system.
The 4th International Workshop on HIV Persistence during Therapy brought together a small group of researchers from academia, government, and the pharmaceutical industry, along with community treatment advocates, to discuss the current state of eradication research.
Part of the difficulty in finding a cure is that scientists do not yet fully understand the HIV lifecycle. Current antiretroviral drugs target specific steps in the viral replication process, but "what we're looking at now is much more complex," said Romas Geleziunas, a researcher at Gilead Sciences in Foster City, formerly with UCSF's Gladstone Institute of Virology and Immunology.
One hypothesis is that existing drugs are not potent enough to completely stop HIV replication in the blood. Several recent studies, however, suggest this is a dead end, since treatment intensification – adding new drugs such as stronger protease inhibitors and integrase inhibitors for people with suppressed viral load – still does not get rid of the virus once and for all.
The New Era Study, currently recruiting participants, will evaluate a combination of four classes of antiretroviral drugs, including the recently approved raltegravir (Isentress) and maraviroc (Selzentry).
"This is the mother of all intensification trials," Geleziunas said. "If it doesn't work, we have to put it to rest and move on."
But many researchers are already moving on, concluding that suboptimal therapy is not the problem. Instead, even after potent drugs clear existing HIV in the blood, latent reservoir cells can pump out more virus and start the replication process all over again – which is why people need lifelong treatment.
Investigators are now looking at several strategies to get at the hidden HIV blueprint, known as provirus, in resting cells. These include agents that alter cell signaling pathways to activate quiescent cells and disrupt proviral infection.
"If we can't wake up these cells, we need to find a missile to attack them," explained Geleziunas. "Once a cell is activated, we hope it will die due to HIV replication or immune response. But we may need to help it die." At the same time, antiretroviral drugs can serve as a "safety net" to protect new cells against infection by released virus.
Much remains to be learned about such agents, including how long they would have to be taken and what kinds of side effects they might have. By activating cells, for example, there is a risk that such drugs could cause cancer.
Forum participants asked about several other potential strategies, including maintaining permanent latency – so reservoir cells never wake up and release virus – and transforming HIV to a weaker form.
The problem with the latter strategy, according to Rick Loftus, an internal medicine doctor at California Pacific Medical Center-Davies and a former member of ACT UP/Golden Gate, is that infecting CD4 cells is not the only way HIV causes harm.
"Even weak, lazy virus may trigger immune activation, which is responsible for a lot of the conditions we have seen in people with HIV," he said.
Scientists are also studying "elite controllers" (the tiny proportion of people whose immune system naturally keeps HIV in check) and the "Berlin patient" – a man who cleared HIV after receiving a bone marrow transplant from a donor with a genetic mutation (CCR5-delta-32) that protects cells from infection – in an attempt to find clues to help others who are not so lucky.
Researchers are also revisiting the idea that treatment during acute or initial HIV infection – using today's new and more powerful drugs – might play a role. UCSF's Options Project and similar trials are enrolling newly infected participants on an ongoing basis.
"I'm willing to bet that might help," said Loftus. "Even if only treated for 12 months, [people who start that early] do have lower viral load and higher CD4s. They may be good candidates for eradication, because they have low reservoirs."
Companies like Gilead are starting to weigh the benefits of developing additional antiretroviral drugs versus looking for a cure. "We should do something cutting edge," said Geleziunas. "Let's go for the whole thing."
But some participants expressed skepticism that drug companies would put adequate resources into HIV eradication without pressure, considering that lifelong therapy may be more profitable than a one-time cure.
"We have seen within the drug industry that while there are scientists with great ideas, management sometimes quashes ideas due to competition with existing products or competing priorities," said AIDS Policy Project's Stephen LeBlanc.
To provide such pressure, APP encourages activists to contact President Barack Obama and ask what he is doing about a cure for AIDS. The group has also filed a Freedom of Information Act request seeking details about research proposals submitted for federal funding.
APP will host a town meeting on AIDS cure research on Saturday, February 20. For more information, see the Guest Opinion on page 4.