"About one in a million T-cells holds latent HIV that the antiretroviral drugs can't touch," said Zack, a professor of medicine and vice chair of microbiology, immunology and molecular genetics at the David Geffen School of Medicine at UCLA. "Our challenge was to make latent HIV vulnerable to treatment without harming healthy cells."
The UCLA researchers created a model using mice specially bred without immune systems. The team implanted the mice with human thymus tissue and then infected the tissue with HIV. The mice responded by producing human T-cells infected with latent HIV.
Zack and Brooks next used a two-step approach to expose and destroy latent HIV. First, they stimulated the T-cells strongly enough to prompt the cell to express latent virus but not to trigger other cellular functions. This revealed the hidden HIV.
Second, they used a new weapon called an immunotoxin — an anti-HIV antibody genetically fused with a bacterial toxin — to target and kill only the T-cells infected with HIV.
"The immunotoxin functions like a smart bomb — the antibody is the missile guidance system and the toxin is the explosive," Zack said. "When the T-cell switches on and starts expressing virus, the antibody binds to the surface of the T-cell, forcing the toxin into the cell and killing it. This prevents the cell from making more virus."
"The beauty of this approach is that it doesn't destroy healthy T-cells — only the ones hiding virus," Brooks said.
Prior to the UCLA discovery, scientists needed to over-stimulate T-cells to force them to express latent virus. This ran the risk of harming the patient by impairing the entire immune system. In contrast, the UCLA model exposed and killed hidden HIV without affecting the rest of the immune system. The T-cells in the UCLA model also did not divide, indicating that they were able to produce virus without behaving as if they were confronting a foreign particle.
"In our mouse model, the two-step approach cleared out nearly 80 percent of the latently infected T-cells," said Zack. "No one has ever been able to achieve this before. We hope that the strategy we've proven effective in the lab will show similar success in people."
This technique still must undergo a lot of development before it is ready for use in humans. One difficulty will be to be able to calibrate how exactly to stimulate human T-cells just enough to get only the desired response. Given that lab animals are less genetically variable than humans the discovery of the correct level of stimulation may be hard to do for each patient. Also, there are plenty of other factors that could make the results harder to duplicate in humans. Still, this is a clever technique.
Humans suffer from a number of other chronic viral infections including oral and genital herpes and various forms of viral hepatitis. The ability to eliminate chronic viral infections would be great for the wider population as well. However, this model doesn't really work for them since this model is specific to T-cells which HIV infects. Still, it does not seem unreasonable to expect that ways will also be found to bring viruses out of hiding in other cell types.
|Share |||Randall Parker, 2003 September 19 11:52 AM Biotech Therapies|