TRAIL ligand induces apoptosis of cells infected with HIV in-vitro

The use of highly active antiretroviral therapy (HAART) has helped to put AIDS into remission for many people who have symptoms of HIV/AIDS.

Unfortunately, taking HAART often means swallowing a handful of pills at regular intervals several times daily, sometimes with food and water restrictions. HAART can also cause side effects, some of which are unpleasant while others are more serious.

Attempts at a cure

Perhaps the most disappointing aspect of HAART is that it does not rid the body of HIV. Proof of this lies in studies where people with HIV/AIDS stop taking their medication (these -drug holidays – are commonly called Structured Treatment Interruptions, or STIs). In such cases virus levels have often surged into the detectable range. HAART is unable to cure HIV infection because the virus can lie low, hiding in some cells of the immune system that are at rest. Because the virus can keep a low profile in resting cells, the immune system does not know that these cells are infected and does not destroy them, allowing HIV to persist. As well, anti-HIV drugs do not work well in resting cells or another group of immune cells called macrophages, which are also infected by HIV.

Although there have been attempts to purge the body of HIV using a combination of HAART and IL-2 (interleukin-2), these have not been successful. Now a team of Canadian scientists has taken a different approach to destroying HIV-infected cells that may be worth testing in HIV positive people.

On the TRAIL, in the lab

Researchers at the University of Ottawa, working in the laboratory of Dr. Andrew Badley, have been studying ways of killing HIV-infected cells using a compound called TRAIL (TNF-related apoptosis-inducing ligand). Technicans collected blood samples from patients who had been taking HAART and who had low levels of HIV in their blood (fewer than 50 copies) for at least a year. Immune cells were removed from the blood samples and exposed to TRAIL in the test-tube for about 12 hours. In analysing their results, the researchers found that HIV-infected T cells (CD4+ and CD8+ cells) had died, while most of the HIV-negative cells lived. Researchers also found that TRAIL was able to kill other groups of HIV-positive cells such as macrophages and memory cells.

How TRAIL works

TRAIL works by causing HIV-infected cells to commit suicide – a process known as apoptosis. What is novel about the Canadian research is that it takes advantage of a natural process and it also works in macrophages. This latter point is important because currently available therapies, and a few in the pipeline, don’t work well in these cells, allowing HIV infection to persist. In theory, TRAIL should be low in toxicity. Studies in healthy mice and monkeys suggest that most versions of TRAIL are not harmful to major organs (liver, kidneys, heart, bone marrow).

What’s next

According to the Ottawa researchers, the next step is to test TRAIL in monkeys infected with a an artificial but lethal virus called SHIV (simian HIV). Infection with SHIV causes AIDS to develop quickly in monkeys. These experiments are underway in the U.S. If they are successful, then studies with TRAIL given intravenously to HIV patients will be next. Because TRAIL also has anti-tumour activity, it is being tested in animals with cancer.

Source: Canadian AIDS Treatment Information Exchange (CATIE). For more information visit CATIE’s Information Network at
http://www.catie.ca