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Prized mice: Paula ­Cannon is using specially bred rodents to test a radical treatment that could lead to an AIDS cure.

In an aging research building at the University of Southern California, a $14.5 million biomedical experiment is under way that until a few years ago would have made many AIDS researchers snicker at its ambition. Mice are the main research subjects (for now), and some 300 of them live in a room the size of a large walk-in closet. Signs plastered to the room’s outer door include blaze-orange international biohazard symbols and a blunter warning that says, “This Room Contains: HIV-1 Infected Animals.” Yet the hazard is accompanied by an astonishing hope. In some of the infected mice, the virus appears to have declined to such low levels that the animals need no further treatment.

This is a feat that medications have not accomplished in a single human, although daily doses of powerful anti-HIV drugs known as antiretrovirals can now control the virus and stave off AIDS for decades. Every person who stops taking the drugs sees levels of HIV skyrocket within weeks, and immune destruction follows inexorably. The lack of a cure–a way to eliminate HIV from an infected person or render it harmless–remains an intractable and perplexing problem.

“This doesn’t look like a multimillion-dollar operation at all, does it?” jokes Paula Cannon, a lead researcher on the project, as she enters the ill-smelling room, which has shelves lined with mice living together in plastic cages that resemble large shoeboxes. As she leads a tour of the cramped space, Cannon wears a face mask, a hairnet, a gown over her clothes, latex gloves, and cloth shoe coverings over her stylish heeled boots. She takes these precautions not to protect herself but to ensure that she won’t transmit a dangerous infection to this colony of mice–which is worth somewhere around $100,000.

The experiment costs so much in part because Cannon and her team had to purchase mice bred to have no immune systems of their own; the AIDS virus normally cannot copy itself in mouse cells, making ordinary mice worthless as disease models. Human immune-system stem cells are transplanted into pups bred from these mice when they are two days old, and over the next few months, those cells mature and diversify into a working immune system. Then the mice are infected with HIV, which attacks the immune cells. But before transplanting the original human cells, the researchers introduce an enzyme that interferes with the gene for a protein the virus needs to stage the attack. This modification makes a small percentage of the mature immune cells highly resistant to HIV, and because the virus kills the cells it can infect, the modified cells are the only ones that survive over time. Thus, the HIV soon runs out of targets. If this strategy works, the virus will quickly become harmless and the mice will effectively be cured.

Results from the mouse experiments are encouraging so far, and Cannon hopes they will lay the groundwork to begin human studies soon. “I want to cure AIDS by my 50th birthday,” she says; she is now 47. And though she says she is only half serious, her ambition is clear: “I’m looking for a home run.”

Seeking answers: In experiments that Cannon and her colleagues are conducting, human stem cells are transplanted into mice that have been bred to have no immune systems. Before the transplant, the stem cells are modified so that a small percentage of the immune cells they give rise to will be highly resistant to HIV. The hope is that the virus will run out of immune-cell targets and quickly peter out, effectively curing the animals.

In the HIV research community, “cure” has long been considered the dirtiest of four-letter words: over the years, various promising approaches have failed, leaving overhyped headlines, crushed hopes, and dispirited scientists in their wake. HIV simply excels at dodging attack, both by mutating and by lying low in a latent, or inactive, form in which it still remains viable. In such a dormant state the virus can survive for decades, completely untouched by the drugs now on the market. Any attempt to flush this latent virus out of hiding risks doing more harm than good: the treatment itself could be toxic, or it could unwittingly strengthen the infection.

But over the past few years, leading AIDS researchers have begun speaking again of the prospects of a cure. For many, such as Cannon, the goal is a “functional” cure that would allow patients to stop taking antiretroviral drugs without risk of harm from the small amount of HIV left in their bodies. Other, more ambitious investigators want to eradicate the virus totally–what they call a “sterilizing” cure; they are buoyed by an improved understanding of what creates and maintains the reservoirs of latent virus. Either way, the goal is to get HIV-infected people off a lifetime course of drugs.

Douglas Richman, a virologist at the University of California, San Diego, who has cared


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Credits: Daniel Hennessy, Tami Tolpa

Tagged: Biomedicine

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