When it comes to AIDS, rodents have a leg up on humans. Rats and mice naturally resist HIV--a situation that has long frustrated AIDS researchers seeking a small animal model for the disease. But now scientists have shown that a genetically engineered rat is susceptible enough to HIV infection that it may be able to help evaluate some AIDS drugs.
Several groups have attempted to engineer susceptible rodents by stitching in various combinations of the genes that make humans vulnerable (Science, 10 August 2001, p. 1034). Progress has been painfully incremental. Four years ago, a team including virologist Oliver Keppler added human versions of two key molecules that the virus uses to infect immune cells, the surface receptors known as CD4 and CCR5. But the virus did not copy itself robustly in these animals, leading to levels of HIV that were orders of magnitude lower than in humans.
This copying process is the target of many powerful anti-HIV drugs known as protease inhibitors, so this rat model could not help evaluate that class of compounds. Because of these limitations, the model also is of little use to study how HIV causes disease. Keppler, who is now at the University of Heidelberg in Germany, and his group are trying to add genes to these transgenics that specifically attempt to get around the remaining blocks. "I'm not naïvely thinking this model is going to be predictive in all situations," says Keppler.
In the meantime, Keppler's group decided to see if the rats could be used to evaluate AIDS drugs designed to cripple HIV long before it starts to copy itself. The researchers tried out the rats with tests of two already approved drugs: T-20, which blocks HIV entry into cells, and Sustiva, which inhibits the necessary reverse transcription of viral RNA into DNA. Both cut HIV levels by more than 90% in the modified rats, as in humans, the team reports online this week in Proceedings of the National Academy of Sciences (PNAS). Experiments conducted directly on immune cells taken from both the rats and humans showed similar results.
It's a good start, says Robert Gallo, the head of the Institute of Human Virology in Baltimore, Maryland, who edited the PNAS paper and whose lab first proved that HIV causes AIDS. "Everybody wants a small animal model," he says. "This is as good as I've seen." The question, notes virologist Nathaniel Landau, an HIV mouse model developer at the New York University School of Medicine in New York City, is whether drug companies will use it. Keppler says he already has been approached by several companies, including one from big pharma.