University of California researchers have shown that a combination of an agent that activates HIV lying dormant in cells, together with a targeted antibody that kill newly produced HIV before it leaves these cells can reduce the burden of HIV-infected cells in an experiment by up to 80%. The technique is likely to reawaken interest in the possibility of reducing HIV reservoirs in the body, and comes in the same week as news that a technique called PET scanning can identify `hot spots` in the body where HIV is concentrated.
Pioneers of both techniques are suggesting that they could eventually be used to reduce the amount of HIV in the body and extend the amount of time that people can spend off treatment.
"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.
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.
The research team used a diptheria immunotoxin (Pseuodomonas exotoxin) linked to an antibody that targets the CD4 binding site of HIV’s gp120 protein. The immunotoxin is able to select cells which are producing HIV without killing uninfected cells. The researchers also used the cytokine interleukin-7 to induce latently infected cells to produce virus without stmulating activation of all T-cells (a measure that would have upset immune function). Prostratin was also tested for the same purpose.
Prior to the UCLA discovery, scientists needed to over-stimulate T-cells to force them to express latent virus. This could impair the whole 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
Source: press release from the University of Califonia
Brooks DG et al. Molecular characterization, reactivation and depletion of latent HIV. Immunity 19: 413-424, 2003.