Sep. 17, 2003 UCLA AIDS Institute scientists have devised a new technique to switch on and drive hibernating HIV from its hiding places in the body. Reported in the September issue of Immunity, the research suggests a possible therapeutic strategy to kill the hidden virus so people who are HIV-positive could eventually stop taking antiretroviral medications.
"Our findings show potential for flushing HIV out of its hiding places in the body," said Dr. Jerome Zack, principal investigator and associate director of basic sciences for the UCLA AIDS Institute. "If our method proves successful, it may enable HIV-infected individuals to discontinue costly and complex antiretroviral therapy, which can cause serious side effects."
"Immune cells can't kill HIV if they can't detect it," said Dr. David Brooks, a postdoctoral fellow and lead author of the study. "By switching on an HIV-positive person's dormant virus, we hope to enable the immune system to recognize and eradicate HIV-infected cells before they spread more virus."
Antiretroviral drugs kill HIV, often depleting the virus to undetectable levels in the blood of people taking the medications. This treatment alone, however, cannot completely eliminate HIV infection from the body.
Latent, or hibernating HIV, still hides in resting T-cells, which quietly lie in wait for a foreign particle to invade the immune system. When a foreign invasion occurs, the event activates some of the T-cells, which promptly begin manufacturing virus. And, when an HIV-infected person discontinues antiretroviral drugs, this small reservoir of latently infected T-cells can rekindle the spread of HIV infection throughout the body.
"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."
Zack and Brooks envision the two-step approach working as a supplement to antiretroviral therapy, and are planning studies on more complex models before progressing to human clinical trials.
"We propose that HIV-infected individuals could use the two-step approach while they take antiretroviral drugs. The medications would stop replication of any virus that the immunotoxin missed," said Brooks. "After the toxin rids the body of all latent HIV, the patient may be able to safely discontinue antiretroviral therapy."
In another possible scenario, physicians might first administer a therapeutic vaccine to enhance the ability of the patient's T-cells to kill HIV-infected cells. This would help the two-step approach rid the body of latent virus more efficiently.
The National Institutes of Health, American Foundation for AIDS Research and the Universitywide AIDS Research Program funded the study. Co-authors included Dean Hamer, the National Cancer Institute; Philip Arlen, Greg Bristol, Lianying Gao and Christina Kitchen, UCLA; and Edward Berger, the National Institute of Allergy and Infectious Diseases.
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