Setbacks and Progress in the Search for an HIV Cure20th International AIDS Conference (AIDS 2014) taking place this week in Melbourne, with scientists reporting both advances and setbacks.
Jintanat Ananworanich, formerly of the Thai Red Cross and now with the U.S. Military HIV Research Program, gave an overview of “Where Are We Now and Where Are We Going?” with cure research at an opening plenary on Monday.
After reviewing some special cases that offer proof-of-concept that it may be possible to control HIV at least temporarily without antiretroviral therapy (ART)—including the Berlin Patient, the Boston Patients, and the Mississippi Baby—she concluded that success will likely require a combination approach, for example, early ART, agents that overcome viral latency, gene therapy to protect CD4 cells from infection, and therapies that strengthen immune response.
Researchers also discussed cure-related work in oral abstract sessions at the main conference and at a two-day pre-conference “Towards an HIV Cure” symposium organized by the International AIDS Society (IAS). Several of them summarized their findings and offered their thoughts about future directions at an IAS press briefing on Monday.
Deborah Persaud from Johns Hopkins gave an update on the Mississippi Baby (now a child nearly four years old) who just before the conference was found to still have HIV after having no detectable virus while off ART for more than two years. This case suggests that HIV establishes latent reservoirs very early—the child started treatment just 30 hours after birth—and even a few remaining infected cells are enough to rekindle viral replication.
Though disappointing for the child, who has resumed antiretroviral treatment and is in good health, Persaud said, “we have learned a lot from this case and it provides a strong rationale for moving forward with a clinical trial” of very early combination therapy for infants.
Dan Barouch from Beth Israel Deaconess Medical Center described a study in monkeys, published this week in Nature, showing that an HIV-like virus seeds itself in cell and tissue reservoirs very soon after sexual exposure—even before viral load is detectable in blood plasma. Very early ART reduced the size of the reservoir, but did not prevent re-emergence of the virus after treatment was stopped. “Even very early is not early enough,” he said.
One challenge in the cure field raised by Ananworanich is that scientists—not to mention regulatory authorities, pharmaceutical companies, and HIV-positive people themselves—do not all agree about the definition of a cure. Experts increasingly agree that complete eradication of every last bit of virus may not be possible, but many people living with HIV would be happy to be able to maintain control of the virus for prolonged periods off ART.
“We’re looking at the moment at achieving long-term remission, and how long can we go [without antiretrovirals],” said AIDS 2014 co-chair Sharon Lewin from Monash University. “We’ve realized in the past year that the virus can really hang around for a very long time and pop up unexpectedly.”
One widely used strategy in HIV cure research is dubbed “kick and kill” or “shock and kill.” This involves using various methods to reactivate latent viral genetic material in resting T-cells. Once this virus “wakes up” and starts replicating, it becomes visible to the immune system and susceptible to antiretroviral drugs.
One type of agent used to reactive latent HIV is histone deacetylase (HDAC) inhibitors. HDACs are enzymes that keep DNA tightly coiled in a cell’s nucleus so it cannot be used to produce new proteins. HDAC inhibitors reverse the process, allowing viral gene expression and production of new virus.
Ole Schmeltz Søgaard from Aarhus University Hospital in Denmark described his team’s research using the HDAC inhibitor romidepsin, which is used as a treatment for lymphoma, to kick cells containing dormant HIV out of their resting state.
In a small study of six patients with long-term viral suppression on ART, romidepsin was shown to increase histone acetylation in lymphocytes, raise levels of cell-associated HIV RNA in CD4 cells, and increase plasma viral load. However, the size of the viral reservoir—as indicated by total HIV DNA in CD4 cells—did not change significantly.
“We have enough data to say the agent was successful in doing what it was supposed to: kicking virus out of cells,” Søgaard said. “We can make cells release virus into plasma, but that may not be enough to reduce the reservoir.”
Steven Deeks from the University of California at San Francisco said this first evidence that we can identify latent HIV and shock it out of hiding in people “is the single most important advance of this meeting.” That’s the shock, he said, “but once [the virus] gets out, we have to kill it.”
Like Ananworanich and most others working on HIV cure research, Deeks thinks a combination approach will be required to achieve a functional cure that allows people with HIV to remain off ART without disease progression. As the virus is released from newly activated resting cells, the immune system will need to be able to recognize and attack it.
“The Mississippi and Boston cases make me wonder if we will ever get rid of the entire reservoir,” Deeks said. “We may get rid of big chunk of it…but we need a way to control what’s left.”
Deeks predicted that the cure field will move in the direction of therapeutic vaccines or other immune-based therapies that can be used in combination approaches. Søgaard’s team has just started a new study looking at romidepsin in combination with the therapeutic Vacc-4x vaccine.
“We should not oppose vaccine and cure research, and probably we will need both,” predicted IAS President Françoise Barré-Sinoussi.
Liz Highleyman (liz (at) hivandhepatitis.com) is a freelance medical writer and editor-in-chief of HIVandHepatitis.com.