Heidelberg scientists develop first transgenic small-animal model for rapid testing of anti-AIDS agents
For the first time ever, a team of Heidelberg scientists headed by virologist Dr. Oliver Keppler has successfully used "transgenic" rats to test drugs combating human HIV infection. The animals had previously been made HIV-susceptible via systematic alteration of their genetic make-up. Accordingly, there is now a transgenic small-animal model available for the swift, large-scale screening of drugs counteracting the AIDS pathogen HIV prior to their use on humans. The article has just been published in the online edition of the renowned American journal "Proceedings of the National Academy of Sciences".
Before new medicinal agents can be tested on healthy probands and patients in clinical studies, they first have to be screened for tolerance and efficacy using animal models. Normally, HIV is not infectious for mice nor rats, only for humans and certain primates. "With the animal HIV models we have so far, efficacy studies are technically intricate, very expensive and highly time-consuming," Dr. Keppler reports. "This has substantially impeded rapid progress in the development of new drugs against HIV." Largely for ethical reasons, routine testing on primates has not been a workable proposition.
Incorporating human genes into the rat genome
Christine Goffinet, Ina Allespach and Privatdozent Dr. Oliver Keppler of the Department of Virology, Heidelberg University Hospital (medical director Professor Dr. Hans-Georg Kräusslich) are investigating whether medicinal agents counteracting HIV infection can be tested on transgenic rats. In conjunction with scientists at the J. David Gladstone Institute in San Francisco, human genes were introduced into the genomes of these rodents, thus making them susceptible to HIV infection. The genes cause "human" proteins (HIV receptor complex) to align on the surface of immune cells of the rats, thus enabling the virus to enter the cells. "Earlier investigations had already indicated that transgenic rats can be infected with HIV," Dr. Keppler notes.
The Heidelberg researchers have now succeeded in curbing HIV infection in the rat model with drugs that have also been used successfully on HIV patients. These drugs, which are capable of delaying the onset of AIDS in humans, either prevent the HI virus from entering the cell or halt its proliferation in cells by inhibiting the reverse transcriptase, a viral enzyme responsible for the transcription of the virus's genetic material. Applying these drugs to transgenic rats brought about an over 90% reduction of the HIV infection level. "Interestingly, the degree of anti-viral efficacy was similar to that achieved in comparable tests of the drugs' effect on HIV-infected patients," says Dr. Keppler. "This is an important finding and promises well for future investigations of new medicinal agents."
With this HIV small-animal model, Dr. Keppler's research group is now conducting efficacy tests on compounds still at the development stage, including inhibitors of the HIV integrase, a viral enzyme responsible for the integration of genetic material of HIV into the genome of the host cell. This transgenic rat model can be expected to help ensure that only the most promising candidate drugs for combating HIV will be selected for future clinical studies on humans, thus accelerating the further development of virostatic agents.
Christine Goffinet, Ina Allespach and Oliver T. Keppler,
HIV-susceptible transgenic rats allow rapid preclinical testing of antiviral compounds targeting virus entry or reverse transcription, Proc. Natl. Acad. Sci. USA, online publication
For more information contact
PD Dr. med. Oliver T. Keppler
Department of Virology
Institute of Hygiene
Heidelberg University Hospital
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