Researchers at the National Cancer Institutes HIV Drug Resistance Program developed RT-SHIV, a virus that acts like HIV when used with drugs. (Photo courtesy of the National Institutes of Health)
PopularMechanics.com, Dec. 1 -- In order to find out how one of the world's most devastating diseases overcomes state-of-the-art drugs, scientists in Maryland are re-engineering the HIV virus. They have combined pieces of HIV and another virus to create a deadly new hybrid--a tenacious little microbe that knows all the tricks of its parent pathogens. Discovering where, and how, HIV hides in the body will be a critical step towards a cure for the disease--or at least a better treatment.
From a medical standpoint, what makes this viral Frankenstein special is that it possesses twin traits not found together in any other virus. First, it can replicate in macaques--monkeys commonly used in medical research--causing an AIDS-like illness. That's crucial, because macaques are ideal vessels in which to study how immune-compromising viruses do their dirty work. Second, the new pathogen is susceptible to a full complement of antiretroviral drugs, the primary tools used to treat HIV-positive patients. This means that, for the first time, researchers can both induce and suppress an ailment that mimics the defining aspects of human HIV infection.
To create the microbe, called RT-SHIV, researchers painstakingly spliced a fragment of genetic material from HIV-1, the main strain of HIV, into the genome of a monkey pathogen called simian immunodeficiency virus--replacing about a tenth of the genome. The added fragment makes the enzyme the target of many antiretrovirals.
The new virus and its monkey counterpart constitute the closest model we have for HIV's response to antiretroviral therapy, says virologist Vineet KewalRamani, whose National Institutes of Health research team in Frederick, Md., created the bug. "Animal models" of disease are vital to medical progress, he notes. They enable researchers to test therapies that might be unacceptably risky to try in people. Scientists are also ethically permitted to harvest biological samples from monkeys that they can't collect from living people.
The hybrid RT-SHIV virus is still too different from HIV to be useful in finding the holy grail of AIDS research: an effective vaccine. (Microscopy courtesy of the National Institutes of Health)
Viral Hide and Seek
RT-SHIV should provide several scientific payouts, experts say. Chief among these, according to Robert Siliciano, a virologist at Johns Hopkins University, is that it could hint at where in the body HIV takes shelter during drug therapy. Doctors have long observed that antiretroviral cocktails can essentially banish HIV from a person's blood. But if the patient stops taking his pills, the virus quickly rebounds, which indicates that it must have been lurking somewhere else.
Researchers like Siliciano have been working for years to uncover HIV's hiding place. One sanctuary, a subset of the immune cells called CD4 cells, has been nailed down. "There's another major reservoir," Siliciano says. "We don't know where it is. We're hoping to use this model to find this second reservoir."
The latest results from the NIH lab, described three weeks ago at a symposium in Chantilly, Va., offer an encouraging sign. RT-SHIV, like HIV, takes cover when it comes under antiretroviral assault. "We have evidence of a reservoir," KewalRamani says. "Now we can try to seek it out."
In their next study, NIH researchers plan to suppress RT-SHIV in infected macaques, using antiretrovirals, then test for which tissues and cell types harbor latent virus. Pinpointing the reservoir in a primate would identify a probable target in people. "Nobody's ever going to be cured unless we get rid of that reservoir," Siliciano says.
Research on RT-SHIV could also improve the success and safety of HIV drug regimens. A major peril for any patient is that HIV can adapt to drugs, eventually becoming impervious to them. But the development of drug resistance is difficult to study in petri dishes, says virologist Paul Bieniasz of the Aaron Diamond AIDS Research Center and Rockefeller University in New York. Drug resistance evolves differently in the lab than it does in the warm environments of human or animal hosts.
KewalRamani's team has found that RT-SHIV, again mimicking HIV, can learn to circumvent drug therapy. Because some experimental drugs completely flop in the clinic, even after showing promise in lab-grown cells, macaques carrying RT-SHIV could provide an important testing ground for future antiretrovirals.
On the other hand, the hybrid virus is too different from HIV to be useful in finding the holy grail of AIDS research: an effective vaccine. For that reason, Bieniasz says, "we'd like to move to a virus that's mostly HIV-1" in its genetic makeup. This October, in the journal Science, his research team reported early steps in that direction. The new virus is not yet ready for an animal model, however--which means RT-SHIV and an army of macaques is still the best hope for defeating the disease with drugs.