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Rooting Out Reservoirs of HIV Infection
Using cell and animal models, Hopkins scientists are seeking drugs that can oust latent HIV from its hiding places.
February 2010 -- Despite the extraordinary success of antiretroviral therapy, there still is no cure for HIV, which currently infects 33 million people worldwide. That’s because, even when the drugs reduce HIV in the bloodstream to undetectable levels, latent virus continues to persist in hidden reservoirs. If a patient stops the antiretroviral regimen, the latent virus will rebound in a matter of weeks.
“Reservoirs of latent HIV are widely recognized as an obstacle to curing anybody of HIV,” says Robert Siliciano, a Howard Hughes Medical Institute investigator in the Departments of Molecular Biology and Genetics and Medicine.
But now, Siliciano and other Hopkins researchers are starting to develop and test strategies for overcoming that obstacle. In a paper published in the November 2009 Journal of Clinical Investigation, Siliciano reports on a plan for identifying compounds that might help eradicate latent HIV.
The problem of HIV latency has intrigued Siliciano for many years. In the 1990s, he became the first to demonstrate the existence of HIV reservoirs, regions where HIV resides in a latent, or nonreplicating, state. Specifically, he showed that a special type of immune cell, known as resting memory T cells, can harbor latent virus.
Tucked away in the DNA of these quiescent cells, the virus stops replicating and thus evades antiretroviral drugs, which target only actively replicating virus. Only about one out of one million T cells may contain latent HIV, but that’s enough for the infection to endure.
A few years ago, Siliciano, working with graduate student Hung-Chih Yang, devised a strategy for rooting out HIV from its reservoirs. Their plan was to find a drug or other mechanism that would reactivate the latent virus. The reactivated virus, they hoped, would then become a target of circulating antiretroviral drugs. Ideally, the reactivated virus would also kill its host T cell so that the cell would not continue to crank out HIV.
As a first step, the researchers have developed a primary cell model of HIV latency. They collected normal T cells from healthy volunteers, infected the cells with HIV, and use molecular tools to induce the T cells to become quiescent. The researchers then isolated the fraction of resting T cells that contained an inactive form of HIV.
Using this model of HIV latency, Siliciano’s team screened more than 4,000 drugs and natural compounds to search for any that would reactivate the latent virus.
The process yielded several promising drug candidates. Of those, the researchers selected one for closer study—a natural toxin called 5HN, which is found in the roots, leaves and bark of the black walnut tree. (Gardeners who have seen plants wither in the vicinity of a black walnut have witnessed the effects of this chemical, which the tree’s roots secrete into the soil.) Those tests confirmed that 5HN activated latent virus and therefore could be used to carry out the group’s strategy for eradicating HIV.
There still is much work to be done before that goal is achieved, says Siliciano. One issue is 5HN’s toxicity. Its potent effects in many plants suggest that therapeutic levels of the compound might cause toxicity in people, too. Even if that is the case, says Siliciano, “We’ve demonstrated proof of principal. Now we can use this system to look for analogs to 5HN that are not as toxic.”
In the next phase of his project, Siliciano plans to use the model to screen one of the vast libraries of candidate drugs maintained by pharmaceutical companies. Perhaps among the millions of compounds in such a collection resides one that can defeat the obdurate reservoirs of infection.
At the same time, Siliciano is also collaborating with Hopkins researchers who have established a model of virus latency in pigtailed macaques. The monkeys are infected with the simian immunodeficiency virus, which causes a disease identical to AIDS in this species.
When the animals are treated with antiretroviral therapy, their active infection declines and residual latent infection remains, just as it occurs in HIV-infected patients, says study leader Janice Clements, professor of molecular and comparative pathobiology. Using the model, she has found that resting T cells aren’t the only reservoir of latent HIV; the quiescent virus also resides in the brain, which may explain why patients on antiretroviral drugs experience cognitive impairment.
Clements, Siliciano and other colleagues just received $8 million from the National Institutes of Mental Health to study latent reservoirs in the brain and other areas, and develop methods for flushing out these reservoirs.