They are the mice that roared five furry warriors in the battle against AIDS whose role in a Texas-based study has strengthened the possibility that common drugs used to treat HIV infection may someday work as a preventive against vaginal transmission of the virus. The results hold promise for millions of women, particularly in the developing world Africa, Southeast Asia and South America where females make up the fastest-growing segments of the HIV-infected population, and public-health workers are desperate to stanch the tide of new infections. "There are 5,700 deaths a day from HIV-AIDS that's the equivalent of an Indonesian tsunami hitting the shore every day," says Dr. Warner Greene, director of the Gladstone Institute of Virology and Immunology at the University of California, San Francisco.
"We are not going to treat our way out of this global epidemic," Greene says. But if antiretroviral drugs (ARVs) can be used as prophylactics, they may help flatten that tsunami wave. "This is one more option while we wait for the development of the vaccine, which has proved to be one of the most elusive enterprises in the history of mankind," says Dr. J. Victor Garcia-Martinez of the University of Texas Southwestern Medical Center and lead author of the new study.
Garcia-Martinez and his team showed that the antiretroviral combo drug Truvada a mixture of two medicines, tenofovir and emtricitabine prevented vaginal HIV transmission in five "humanized mice," when it was given daily for seven days before exposure to the virus. By contrast, seven of the eight mice exposed to the virus but not treated with Truvada acquired HIV infection. The findings, published online this month in PLoS Medicine, were hailed as "fantastic news," says Greene. And, indeed, the study appears to have produced a vital weapon in the AIDS war not only in its encouraging end results, but perhaps more so in the pioneering little lab mice it used to achieve them.
The test mice were actually human/mouse chimeras, which were created in 2006 by the same Texas team, along with colleagues at the University of Minnesota. Before the development of these "BLT mice" for bone marrowliverthymus research in transmission prevention was difficult and expensive at best: Aside from macaque monkeys, which could be infected with SIV, a primate-specific version of HIV, most lab animals couldn't be studied because of their natural invulnerability to the human virus. Garcia-Martinez' humanized BLT mice, however, were genetically engineered to develop a nearly human immune system complete with the dendritic cells, CD4+ T cells and macrophages involved in HIV transmission and infection. The new study showed that BLT mice were susceptible to vaginal HIV infection, just like humans, and that the symptoms of their infection looked a lot like they did in people a "very valuable model system," says Greene.
The mice will soon be made widely available to other labs. "There will be new cures, new treatments," Garcia-Martinez says. "Researchers can only be restricted by how far out of the box they can think." Still, he is quick to point out that human study is needed before any real treatment promises can be made. "This human/mouse chimeric model ... at end of the day, they are mice," he says. Garcia-Martinez' team is now working on development of a BLT mouse that can be infected rectally.
Meanwhile, the Texas study will help resolve dosage and drug-delivery issues in human clinical trials on ARVs under way in the U.S., South America and Africa. Results from the current trials are expected over the next three years, and if they also show that ARVs are effective prophylactics, doctors may begin using them in women who are most at risk. Half of all new HIV infections in the world occur in women many of them living in societies where they have little influence over the habits of their sex partners. "That's why condoms haven't stopped this epidemic," Greene says; nor has male circumcision a procedure that studies suggest can cut the infection rate in men by 50%, but that women cannot force upon a husband or partner.
So, while millions of women along with the rest of the world wait for news of a vaccine, doctors hope that an ARV pill, or combination of pills, may be used as a viable stopgap and a way to give people a hand in their own physical destiny. "I think it could empower women," says Greene.