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UCLA Scientists Solve Mystery of How AIDS Virus Evades Anti-HIV Drugs in the Body
For the past 20 years, HIV's ability to sidestep powerful anti-AIDS drugs by hiding dormant in the body has frustrated scientists. Today, a mouse model described by UCLA AIDS Institute researchers in the journal Nature Medicine illuminates how the virus exploits the human immune system to hibernate and avoid the drugs -- then virulently resurface years after initial infection.
"Even when we can't detect HIV in the blood of patients taking anti-AIDS drugs, we know that dormant virus continues to lurk elsewhere in the body," explained Dr. Jerome Zack, associate director for basic sciences at the UCLA AIDS Institute and principal investigator.
"But until now, no one understood how the AIDS virus evades the drugs, resurrects itself from a resting state and spreads infected cells throughout the body," added Zack, a UCLA professor with dual appointments in the Departments of Medicine, and Microbiology and Molecular Genetics. "These findings mark a huge leap forward."
Current anti-AIDS drugs prevent HIV from spreading new infection, but have no effect on cells already infected. Unfortunately, researchers' study of latent virus has been stymied by their difficulty at finding dormant infected cells in the body. In the blood of an HIV-positive person, fewer than one in a million cells hold latent virus.
As an immunologist, Zack focuses on the thymus, the organ that transforms immature bone-marrow stem cells into the mature T-cells that HIV targets. He saw a possible parallel between the fluctuating activity levels of T-cells during development and the fluctuating activity level of AIDS virus in the body.
"Young T-cells start off highly active, then slow down as they mature," Zack explained. "When they leave the thymus and enter the blood, they circulate in a resting state until confronted by a cell-specific foreign particle - or antigen - which awakens them for attack.
"If HIV invades the thymus, the organ will begin producing HIV-infected T-cells," he said. "Similarly, these T-cells would mature, disperse and hibernate in the blood until awakened by the antigen. Only this time, the antigen would switch on the cell and virus simultaneously. This would explain the sudden rebirth in HIV activity."
To test his theory, Zack and colleague David Brooks created an experimental model with mice that are specially bred without immune systems. Because HIV cannot infect mice, the researchers implanted the mice with human thymus tissue, which began producing human T-cells.
The researchers injected HIV into the implant and waited for the infection to spread. Then they harvested infected human T-cells from the thymus tissue, deposited them in a culture dish, and immediately added HIV-fighting protease inhibitors and AZT. These drugs prevent the virus from spreading to other cells, simulating the condition of a person on antiretroviral therapy.
Next, the UCLA team measured the amount of AIDS virus expressed by the cells before and after stimulating them with agents that imitate confrontation with a T-cell specific antigen.
What they saw surprised them. Within 24 hours after stimulation, the cells' expression of viral genes jumped 30-fold. Within three days, nearly 20 percent of the cells began expressing HIV proteins.
In comparison to HIV-infected patients' blood -- which contains fewer than one latent cell per million -- the UCLA model identified one latent cell out of five, making researchers' efforts to study the virus dramatically easier and faster.
"We knew that reactivating the cells with antigen would switch on HIV gene expression," Zack admitted. "But we never expected to see such a striking increase."
This proved two things, according to Zack. "First, it shows that thymus cells contain dormant HIV infection," he said. "Second, it confirms that HIV exploits the thymus as a breeding ground for latently infected immune cells."
Lastly, the UCLA team tested whether cells infected with latent HIV were able to leave the thymus and enter the bloodstream. Zack and Brooks removed human T-cells from the mouse's blood and spleen, then stimulated the cells. These cells also switched on and expressed AIDS virus, confirming that the cells had traveled from the mouse's HIV-infected thymus.
"Because our earlier research proved that the thymus remains active until late in life, these findings suggest that the thymus provides a continuing source of latent AIDS virus in the body," Zack said. "We think we've solved part of the mystery of where latent cells come from."
Equally important, the UCLA model provides researchers with a tool for testing the effect of new therapies to target latent HIV in the body, as well as to study how latent viruses behave in T-cells. "We will use this model to test the effect of new therapies on dormant HIV in the body," Zack noted.
The National Institute of Allergy and Infectious Diseases and the Elizabeth Glaser Pediatric AIDS Foundation funded the study.
-UCLA-
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