By E.J. Mundell
Friday, January 5, 2007 12:00 AM
THURSDAY, Jan. 4 (HealthDay News) -- In the hide-and-seek game played out between scientists and HIV over the last 25 years, the virus has so far been winning.
"All of the drugs that we have now are specific antiretroviral agents that inhibit some step in the virus' life cycle, so they hit HIV only when it is replicating," explained researcher Paul Bieniasz, an associate professor at the Aaron Diamond AIDS Research Center in New York City.
That strategy has brought many infected patients long-term health.
"But there's always a small but significant population of virus present in infected individuals that is not replicating," Bieniasz said.
For patients on effective drug therapy, that means HIV remains dormant in tissues at levels that are undetectable by standard tests.
These tiny reservoirs of "latent" HIV lie curled up as bits of foreign DNA buried deep within the nucleus of cells. Like a tiny time bomb, this dormant virus may stay sleeping for years. On the other hand, it may also switch over to replicating status and re-start the deadly progression to AIDS.
"It's a tricky virus, and latency is an excellent strategy for HIV," said Dr. Rowena Johnston, director of basic research at the Foundation for AIDS Research (amfAR). "If the virus is latent, not only is antiretroviral therapy not going to get at it, but it's also impossible for the immune system to target it, too."
Latent virus is the major reason why scientists have failed to find a cure for HIV/AIDS. According to Bieniasz, latent virus has no real "hook" for drugs to latch onto. And because latent HIV lies deep within the nucleus, any drug that could attack it might prove far too toxic to healthy cells.
But that isn't stopping researchers from pursuing a solution to the problem.
"At amfAR, we like to think that if we haven't proven that it's impossible, then we're not doing our job if we don't go after it," Johnston said.
In fact, amfAR is funding the work of Bieniasz' lab, where researchers are creating artificial pools of latent virus in cell cultures. They are using these cultures to test the effects of thousands of compounds -- watching to see if any particular molecule pushes latent HIV into an active, replicating state.
"It's thought that one strategy to eradicate HIV and effectively cure people is to make these latent viruses replicate," Bieniasz said. "Because once they replicate, you can then hit them with existing antiretroviral drugs."
The cell cultures in the Aaron Diamond lab are engineered to switch on a fluorescent biochemical tag, if and when a candidate molecule flips the virus from latency to replication.
Bieniasz said a cure for AIDS isn't around the corner, but these experiments are a vital first step. "What we are looking for here is essentially proof-of-principal that you can do this without having wide-ranging effects on cells," he said.
Other research is also yielding valuable clues to latency.
Dr. Stephen Deeks is an associate professor of medicine at the University of California, San Francisco's General Clinical Research Center. His work, also funded by amfAR, focuses on that tiny minority of HIV-infected individuals -- less than 1 percent -- who have remained healthy for more than 20 years without the need for drug therapy.
These so-called "elite controllers" typically carry virus that stays at low or undetectable levels. "So, the question remains, what makes these individuals different?" said Deeks.
"One model is that they have an immune system that allows them to control the virus very effectively," he said. In fact, some -- but not all -- of these people have immune cells that are especially rich in HLA receptors. "These receptors allow immune cells to recognize very specific parts of an infection, such as a virus," he said.
That could be part of the story. Or, these individuals might have been lucky enough to contract what researchers call a "replication-impaired" form of HIV -- a kind of weakling strain that is easy to keep at bay.
"That remains a theory," Deeks said, "mainly because the virus is actually very hard to find in these individuals. But we are aggressively trying to find that out."
The answers his team comes up with could help the 99 percent of infected patients with no such defenses against HIV.
"If it's the immune response that's key, and if we can figure out what those responses are, then we can develop vaccines that focus in those areas," Deeks said. Vaccine research could also receive a boost if it's a particular strain of virus that causes long-term control, he said.
Cutting-edge drug therapies have already beaten HIV down to infinitesimally low levels. In 2005, a team led by Dr. David Margolis of the University of North Carolina made a big splash by announcing in theThe Lancetthat it had significantly depleted levels of latent virus in four patients.
In the study, Margolis' team added a common epilepsy drug, valproic acid, to the patients' standard mix of antiretroviral drugs. All of the patients had already exhibited very low viral loads for years.
Valproic acid is known to inhibit an enzyme called histone deacetylase 1 (HDAC1), which HIV needs to stay hidden in cells.
By the end of the four-month trial, reservoirs of latent HIV in immune CD4 cells had been depleted by 75 percent, the researchers reported. "This new approach, in the future, may allow us to make progress in eradication of infection in an HIV-infected person," Margolis toldHealthDayat the time.
Still, experts say the bulk of latent HIV hides out in a wide variety of tissues, including the gut, lymph nodes, and drug-impermeable areas such as the brain or testes. So, this line of research still has a very long way to go, according to amfAR's Johnston.
"I don't want anyone to come away with the impression that amfAR thinks that we're close to a cure -- we're absolutely not," she said. "We need to work at understanding what the barriers are, let alone work out how to overcome them."
Deeks agreed. But he also agreed that the search for a cure must go on.
"All of this has to be put into the context of the fact that antiretroviral treatment, although it works great, has its limitations," he said. "Many people can't adhere to these drugs for a lifetime, they are complicated, and all these toxicities keep piling up."
"A drug-free way to manage patients is a highly desirable thing," Deeks said. "I'd call that a cure. And that's what we should be reaching for."
For more on HIV research, visit the U.S. National Institute of Allergy and Infectious Diseases.
SOURCES: Rowena Johnston, M.D., director, basic research, Foundation for AIDS Research (amfAR), New York City; Paul Bieniasz, Ph.D., associate professor, Aaron Diamond AIDS Research Center, New York City; Stephen Deeks, M.D., associate professor, medicine, General Clinical Research Center, University of California, San Francisco; David Margolis, M.D., professor, medicine and public health, University of North Carolina, Chapel Hill