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Research Laboratories.

But safer methods of rousing latently infected cells could now be within reach. “In the last 10 years, there have been enormous new insights into transcriptional control mechanisms of HIV,” says Jonathan Karn, who studies HIV gene expression at Case Western Reserve University in Cleveland. “That’s been feeding indirectly into understanding latency and how you silence the virus and how it becomes reactivated.”

Hazuda is now collaborating with Karn, Margolis, Richman, and other academic researchers to seek new drugs that can flush latent reservoirs. She’s scouring Merck’s shelves for promising experimental compounds as well as drugs that have already made it to market for other diseases. And she expects more companies to join in soon, partly because testing methods have lately made great strides. Powerful new drug screening assays have been introduced, and novel monkey and mouse models are available. New techniques in genomics and systems biology may also reveal biomarkers that allow researchers to gauge whether potential drugs have had an impact on transcription of the latent virus. “How do you show you’ve done something meaningful other than take people off drugs and pray the virus doesn’t come back?” asks Hazuda. “That isn’t a very scientific way to do things.”

Even Siliciano, once a skeptic about eradication, now has his lab searching for antilatency drugs. “I’ve changed because I was really impressed by how easy it was to find compounds that would reverse latency in the test tube,” he says.

Testing Hope

There is no cure for polio, hepatitis B, measles, chicken pox, influenza, and a long list of other viruses. Though the immune system and drugs can ultimately defeat many viruses, they are notoriously difficult to stop before they cause damage–especially a virus that integrates itself into chromosomes and can lie dormant for years. So it’s no surprise that a cure still sounds far-fetched to many experts. Progress, if it occurs, will probably move in fits and starts, especially given the frequent disconnect between what happens in lab experiments and in humans. But the astonishing success of the Berlin transplant suggests that it’s possible, and the limitations of the best available drugs show that it’s necessary.

If Paula Cannon and collaborators at the City of Hope National Medical Center in Duarte, CA, receive a green light from the U.S. Food and Drug Administration, they plan to begin testing their gene therapy in a small number of HIV-infected adults who, like the Berlin patient, need ablation and a bone-marrow transplant to treat cancer–in this case, a B-cell lymphoma. The subjects’ own stem cells will be modified with the zinc finger nucleases that disrupt the gene for the CCR5 receptor. The protocol will be extremely conservative. The patients’ stem cells will be harvested four times, and as an insurance policy, the researchers will keep the first batch–the best ones–in reserve, untouched, in case something happens to the genetically engineered cells. Cannon also plans to stitch the zinc finger nuclease into an adenovirus to mimic a technique that has already received approval in Carl June’s studies.

Cannon is confident that the human studies will prove the merits of the idea, even if it’s only on a modest scale at first. “Our little piece of the puzzle is that we’re trying to get zinc finger nucleases to work in stem cells and not do any harm,” she says. If her research group can crack open the door, she predicts, colleagues will come rushing in to help find more effective, safer, cheaper ways to functionally cure HIV-infected people of all ages everywhere. “There’s nothing like success to galvanize the community,” she says. “If we can produce a one-shot treatment that basically means people don’t have to take antiretrovirals, it’s going to spread like wildfire.”

Jon Cohen, a correspondent with Science, has written for the New Yorker, the Atlantic Monthly, and the New York Times Magazine. He is the author of Shots in the Dark: The Wayward Search for an AIDS Vaccine. His latest Book, Almost Chimpanzee, comes out in September.

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Credits: Daniel Hennessy, Tami Tolpa

Tagged: Biomedicine

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