Researchers at University of Rochester Medical Center reported yesterday a drug used to treat parasitic infections in developing countries also attacks the human immunodeficiency virus (HIV) in a new and powerful way.
Past research has established that HIV has “learned” to hide out in certain human cells where it is safe from the body’s counterattack, cells that come to serve as viral reservoirs. Operating from these havens, the virus slowly builds its numbers over more than a decade until it finally becomes capable of dismantling human immune defenses. In the end stages, this process leaves patients vulnerable to the opportunistic infections of AIDS.
The new University of Rochester study explains for the first time how the virus makes chemical changes that keep its chosen reservoirs alive long past their normal lifespan. The report also provides the first evidence that an existing ant-parasite drug can reverse this process.
“AIDS continues to take nearly 3 million lives worldwide each year, and novel treatment approaches are urgently needed,” said Baek Kim, Ph. D, associate Microbiology & Immunology professor in the at the University of Rochester Medical Center, in a press release issued yesterday.
“We think our results are profound because, in discovering exactly how HIV hides in the body, we think we have learned how to take away its hiding places. Without them, the virus would have a much harder time causing disease,” said Dr. Kim, the study’s lead author.
Cell division is a process central to life. A parent cell divides into two cells, each containing copies of the same genes. This enables a single-cell human embryo to divide and grow into the vast number of cells that make up the human body. Different cell types divide at various speeds. T cells, for example, sense foreign organisms have invaded the body, and quickly divide and grow into a large, specifically designed army to attack the invader. Macrophages, on the other hand, are designed to roam the body engulfing and digesting dead tissue and bacteria. To assume this special role, they give up the ability to divide.
Unlike most viruses in its family, HIV has the ability to infect both non-dividing macrophages and rapidly dividing T cells, a key to its deadliness. Given its choice, HIV would prefer to infect rapidly dividing T cells, because with each division comes another opportunity for the virus to copy itself using the T cells’ genetic machinery. On the other hand, T cells sense they are infected and quickly commit suicide, taking out the virus as well. So quickly do T cells self-destruct that the virus would lose its battle with the human immune system if it did not have long-lived macrophages to hide in during the early years of infection, Kim said.
Many cells can “choose” to die when they sense cancer-causing flaws in their own genes, or when they are being used as a virus factory. Certain biochemical pathways call for cell suicide and others postpone it, with the two forces counterpoised to control lifespan. Cancer and AIDS result in part from problems in these pathways.
Past studies found that HIV-infected macrophages can serve as viral reservoirs because some unknown factor extends their lifespan.
However, Dr. Kim’s research shows that HIV produces a protein that turns on a particular cell-survival pathway. After a multistep process, it ultimately activates an enzyme called Akt that in turn prevents cell suicide.
“Up to now, nobody has really thought about how to eliminate the macrophage reservoir,” Dr. Kuan-Teh Jeang, an HIV specialist at the National Institutes of Health, told Associated Press. “The imagination now has turned toward, ‘How do we eliminate reservoirs?’ … The best way to address our problem is to simply kill those cells.”
The discovery was good news, Dr. Kim said, because the Akt pathway is also a culprit in the development of certain cancers. Indeed, oncologists have been trying to target this pathway for some time in developing potential cancer treatments.
In the next phase of his study, Dr. Kim put human HIV-infected macrophages in lab dishes and added drugs known to block the Akt pathway, to determine if any killed the cells. The experiment worked, with both miltefosine and the related drug perifosine both rapidly killed the macrophages, thus depriving HIV of this hideout.
Perifosine is currently being studied as a possible cancer treatment, and miltefosine is known to be safe through its use in leishmaniasis patients. Kim’s goal is to rapidly study miltefosine in animals to determine if it targets infected macrophages well enough to test in HIV patients.
“The evidence they show is in fact pretty good,” said NIH’s Jeang, who says the next step should be a test of miltefosine in monkeys infected with SIV, the monkey version of the AIDS virus.
The research was published online in the open access journal Retrovirology. The full report can be viewed at http://www.retrovirology.com/content/pdf/1742-4690-5-15.pdf
The University of Rochester Medical Center’s full press release can be viewed at http://www.urmc.rochester.edu/pr/news/story.cfm?id=1853
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