A humanized mouse. That’s what the laboratory of J. Victor Garcia-Martinez created: a mouse with a fully functioning human immune system. It’s the first animal model of its kind and has opened new doors to research possibilities, especially for HIV. And the Garcia lab has used the model to find that an existing drug can prevent HIV transmission. For the past decade, scientists have been able to transplant human cells into mice to study diseases particular to humans. That’s what Garcia-Martinez and his lab set out to do — create a mouse with human T cells in its blood and other lymphoid tissues. But they wound up making something much better.

First they surgically implanted tiny pieces of human liver and thymus tissue under the kidneys of mice that were genetically immune deficient — the mice didn’t have B cells and were missing thymuses, the organ that produces T cells. Then the team transplanted human hematopoietic stem cells into the mice’s bone marrow. In a few days, each mouse started generating an entirely new thymus. Garcia-Martinez and his lab call their animals bone marrow/liver/thymus, or BLT, mice.

“The thymus is not like human,” Garcia-Martinez says. “It is human. It looks exactly like a human thymus.” Just smaller.

Because HIV researchers know that HIV destroys a significant part of the immune system that is housed in the gastrointestinal tract, Paul Denton in Garcia-Martinez’s lab checked the mice after the transplants to see if human lymphoid cells — including T cells and B cells — had populated the large and small intestines. And there they were. “This was a huge surprise to us and everyone in the field,” Garcia-Martinez says. “We found human T cells in places where nobody would even have looked for them. Nobody anticipated that the distribution of human cells in a completely different species would be almost exactly the same as in humans.”

His lab then checked for human cells in the rectums and female reproductive tracts of the mice. Human cells were there too, which meant that for the first time researchers could study HIV transmission in an animal model.

Scientists from around the world have since come to Garcia-Martinez’s lab to learn the technique firsthand, because the mice can’t be bred. If you want a BLT mouse, you must surgically implant human tissue and perform a bone marrow transplant into each mouse. It’s a laborious process, but one that Garcia-Martinez says is well worth it.

Once they mastered the procedure, Garcia-Martinez decided to up the ante. “We wondered if we could prevent HIV transmission in these mice using the same drugs we use for treating patients.”

After HIV enters the body it uses an enzyme called reverse transcriptase to copy itself backward from RNA to DNA. If that first step of the virus life cycle is completed, then the virus is on its way to spreading and eventually infecting T cells, leading to full-blown AIDS. Right now, some of the drugs doctors use to treat HIV — including a common therapy called Truvada — inhibit reverse transcriptase and stop the virus from destroying T cells. Garcia-Martinez’s team wondered if Truvada could block reverse transcriptase before HIV took hold inside the humanized mice.

In one experiment, the lab gave Truvada to one group of mice but not another. Then both groups were exposed to HIV vaginally. All the mice that were given Truvada were protected from infection. Most of the mice in the other group got HIV and developed symptoms similar to those found in humans.

The lab then found that Truvada provided 100 percent protection against rectal HIV transmission, the most common way HIV is transmitted in the United States. Still, Garcia-Martinez was concerned that the drug might not have been distributed throughout the entire body, which is what has to happen in HIV patients. To quell that concern his lab gave mice a dose of Truvada and then injected them with HIV intravenously so that the virus could theoretically go anywhere in the body. Even though the dose of HIV was hundreds of times greater than is typical during human transmission, the mice were protected 90 percent of the time.

These findings have added weight to the idea that HIV treatments could help prevent HIV transmission in humans — something that previous clinical trials had been unable to substantiate.

But while Garcia-Martinez’s team was proving that Truvada protects mice from HIV, researchers from around the world were conducting a large clinical trial in South Africa to see if a topical gel made with small amounts of tenofovir — one of two compounds found in Truvada — could prevent HIV transmission in women who face a higher-than-normal risk of contracting HIV.

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It’s difficult to get accurate results from such trials, Garcia-Martinez says. First you have to enroll a large number of people — 889 women, in this case. Then researchers have to make sure the women use the gel properly, use correct amounts, and apply it at the right time (up to twelve hours before having sex). Researchers educate the women on risk-prevention behaviors. Also, Garcia-Martinez says, it’s impossible to know whether all participants follow proper trial protocol.

Still, researchers announced in July 2010 that the tenofovir microbicide was 39 percent effective in reducing a woman’s risk of contracting HIV. At that rate, the gel would protect more than half a million South African women from getting HIV over the next decade. The researchers also found that there was a 54 percent reduction in HIV infections when women used the gel more than 80 percent of the time.

“These are great and highly encouraging results,” Garcia-Martinez says. Still, he admits that big questions loom. If a lot of people use a tenofovir gel, could the virus mutate and become drug-resistant? If so, would that mutated virus be strong enough to be transmitted from person to person? Would a pill work better than a gel? Would a combination therapy such as Truvada be better than a single compound such as tenofovir? These are questions that the humanized mouse model could help answer, Garcia-Martinez says.

“For the first time we are one step ahead of the virus,” he says. In the past, researchers would create a drug, introduce it to humans, watch as HIV mutated into a drug-resistant strain, and then try to come up with better drugs. “Now we can use humanized mice to anticipate the problems. Are those new strains transmissible? Are they really going to be a health problem? We don’t know. But because of the humanized mice we can test it.”

And Garcia-Martinez is not shying away from the biggest question of all: can people with HIV and AIDS be cured?

Right now antivirals such as Truvada can drive down a patient’s viral load to nearly undetectable levels. But HIV is there in a state scientists call latency, which means that the virus has infected some cells but hasn’t damaged or killed them yet. It just sits there. No known drug can get at those latent cells. But if a patient stops taking medication, the virus will damage or kill those cells, and HIV will spread throughout the body.

It’s not easy to study latency in humans. “How do you go into a human and find the virus in the liver or the lung or the lymph nodes?” Garcia-Martinez says. But by using humanized mice, scientists can search for ways to drive the virus out of latency in a living organism.

“We are only limited by our own imaginations,” Garcia-Martinez says. “This is our charter: to cure a mouse under any circumstances and then translate that into humans.”

J. Victor Garcia-Martinez is a professor of medicine, and Paul Denton is a research instructor, both in the School of Medicine. They received funding from the National Institutes of Health and the Foundation for AIDS Research.