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Killing HIV by Luring It out of Hiding

January 2013 -- The sheep and goats didn’t look good. Their bodies were gaunt, and with each step, their hind legs wobbled. Scans revealed dark lesions in their brains.

HIV gets into the brain HIV infects macrophages, a type of white blood cell, which carries the virus to the brain through the bloodstream. Photo courtesy of the National Science Foundation.

As a postdoctoral fellow at Johns Hopkins in the late 1970s, Janice Clements first encountered these animals in the lab when she began researching how the animals’ disease — known as visna-maedi — reached the brain. Visna is a type of slow-moving virus known as a lentivirus. Animals can be infected for years before showing any signs of illness, and dementia typically shows up as one of the last symptoms, if at all. Clements, a molecular virologist, was tasked with analyzing the biochemical makeup of infected brain tissues to understand the progression of the disease. At that time, researchers hoped visna would provide insight into multiple sclerosis in humans, as both diseases damage the myelin sheaths on neurons in the brain. However, in the early 1980s, Clements’ research into visna was abruptly cut short when a patient appeared at Hopkins with a new type of dementia. The trajectory of his disease, and that of later patients’, resembled what Clements had observed in her sick sheep and goats — except that the patients harbored an entirely different disease. The disease was human immunodeficiency virus, or HIV, and Clements was the first to report that it, like visna, is a lentivirus. That meant that patients would suffer physical deterioration before succumbing to neurological symptoms years later. It also suggested that, like visna, HIV could elude drugs by hiding out in the tissues. But, most importantly, the finding suggested that it would be hard to create a vaccine for HIV.

Viruses enter a cell through a specific binding site, much like a paired lock and key. Vaccines thwart viruses by prompting the body to produce antibodies that block the keyhole. Many viruses respond over time by changing those binding sites — or evolving — within populations. (That’s why flu shots must be updated every year.) But lentiviruses change those binding sites within individuals, making a generic vaccine near impossible. What’s more, lentiviruses also contain proteins that prevent their host cells from producing antibodies. Researchers cannot create a vaccine that mimics the body’s natural immune response if the body has no natural immune response, explains Clements.

Clements and her colleagues immediately recognized that HIV’s new categorization was bad news. “We actually predicted that getting a vaccine would be a lot harder than people working on vaccines thought,” Clements says. 

In 1992, Clements began working with Christine 'Chris' Zink, a veterinary pathologist and now director of the Department of Molecular and Comparative Pathobiology — a position that Clements herself held from 2002 to 2008. Together, they designed a research program and became the first women to receive both a program project grant and a training grant from the National Institutes of Health. With that seed money, Zink and Clements set out to study HIV in the brain. Because only 30 percent of people with HIV suffer from neurological problems, HIV researchers tend to ignore the central nervous system (CNS), Zink says. However, understanding what HIV does to the CNS is critical, as the virus can linger there unnoticed for years.

Janice Clements Janice Clements

Since rodents, typically the research animal of choice, are immune to HIV, the two women began working with monkeys. Monkeys can be infected with simian immunodeficiency virus (SIV), which is HIV’s ancestor. As in humans, only a handful of SIV-infected monkeys developed neurological problems, and those problems took two to three years to emerge. Zink and Clements needed a better model. They knew that passing a virus from animal to animal makes the disease more virulent, so they transferred SIV along a line of rhesus monkeys. Then they had a stroke of luck: As part of a different experiment, another researcher borrowed their virus and injected her own strain of SIV as well as the Hopkins SIV into a different species of macaque monkeys.  Within three months, 90 percent of the monkeys had developed neurological problems. “We had our model,” Zink says.

Then, in the mid-1990s, powerful anti-retroviral drugs for HIV hit the market. The virus went from being a death sentence to a manageable chronic disease. Zink and Clements wanted to study the effects of anti-retroviral drugs on SIV in their monkeys, but the drugs didn’t always work the same way in the animals. Nor were the monkeys terribly cooperative. “You can’t just ask a monkey to take a pill,” Zink laments. Over time, the women identified two classes of drugs for SIV, those that entered the brain and those that did not. In 2010, Zink demonstrated that minocycline, an antibiotic commonly used to treat acne, can lessen inflammation in the brain triggered by HIV. Minocycline continues to be studied for its ability to lessen inflammation in the brains of HIV-infected individuals.

Chris Zink Chris Zink

Recently, Luna Alammar-Zaritsky, then a graduate student in Clements’ lab, figured out why HIV takes so long to cause neurological problems. She found that initially the body’s innate immune response can control the virus in the brain and keep inflammation in check. But as the years wear on, the brain gets overloaded and that anti-inflammatory response wanes. “In the brain, the virus is handled very differently than in the body,” Clements says.

In their latest endeavor, Zink and Clements are going for gold: They’re looking for a way to cure HIV. For a long time, Zink says, talking about a cure was out of vogue; most researchers thought that the best hope was to develop a vaccine. And then along came Timothy Ray Brown, a.k.a., The Berlin Patient. Brown had been carrying HIV for more than a decade when he was diagnosed with leukemia in 2006. He received a bone marrow transplant from a donor who did not carry the receptor (CCR5) that mediates entry of HIV into cells. Brown’s HIV vanished. Bone marrow transplants are extremely risky and cost hundreds of thousands of dollars, making them unfeasible for widespread use against HIV. But Brown’s story, Clements says, provided “a proof of concept that you could actually eradicate the virus.” 

Now, researchers around the world are working to turn that concept into reality. Some are conducting genetic modification experiments that cleave out the receptor that binds HIV. Zink and Clements’ lab is part of a collaborative $32 million project aimed at bringing the virus out of its hiding spots in tissues, including hard-to-reach brain tissue, and then zapping it with drugs to kill it off. Specifically, it’s known that antabuse, a drug used to quell the urge to drink in alcoholics, activates the HIV virus. So Zink and Clements want to see what happens when their infected monkeys receive antabuse followed by anti-retrovirals. “The theory is if you can get the virus to come out and kill it, you might be able to eradicate the virus from the body,” Zink says.

Both Clements and Zink remain committed to studying HIV’s often hidden agenda in the brain. Their unique partnership provides the perfect setting in which to examine HIV through a distinctive lens.  Says Clements, “Our collaboration has provided the opportunity to examine the mechanisms by which HIV causes disease to a depth that would not have been possible if she just had her lab and I had my lab.” 

 –Sujata Gupta

Related Stories:
Antibiotic Might Fight HIV-Induced Neurological Problems

Q & A with Janice Clements on how HIV infects the brain

Q & A with Chris Zink on being a veterinarian HIV researcher

Q & A with Joseph Mankowski on investigating HIV and the journey from veterinarian to researcher