Researchers may have figured out how HIV kills white blood cells and causes AIDS:
Scientists have long known that HIV sets up little biological factories inside the the body’s protective CD-4 T cells they infect, producing millions of copies that eventually lead to a massive destruction of the immune system. Until now, investigators have not understood why the virus becomes so aggressive. It turns out HIV, which infects only a small number of T cells at the start, destroys approximately 95 percent of immune cells through a process known as the bystander effect.
Warner Greene, head of virology and immunology at the Gladstone Institutes in California, says bystander cells that are in the neighborhood of HIV-infected cells succumb to a fiery death. “Most CD4-T cells during HIV infection die not because of the toxic effect of the virus, but because of an immune response against the virus. So, CD4 cell depletion is more of a suicide than a murder,” said Greene.
This violent immune response seems to contribute to the progression of the disease:
The response is a self-destruct protocol called pyroptosis. In contrast to the better-known apoptosis, in which cells die quietly without triggering inflammation, pyroptosis is “not a bland, but a fiery death,” Greene says. These cells spew inflammation-causing chemicals as they die, attracting more T-cells that can then become infected themselves by the newly freed HIV. “In a bacterial infection, recruiting all these cells might be a good strategy for containing the infection,” Greene says, but with HIV a vicious cycle of infection results. Pyroptosis also explains why AIDS is associated with high levels of inflammation.
This finding may lead to new HIV therapies:
Greene thinks that pyroptosis (or the lack of it) could explain why HIV usually causes AIDS in humans but its relatives, the SIVs, barely sickens the apes and monkeys that they infect. SIVs can kill CD4 cells directly, but they can’t trigger the same pyroptosis response in other primates. They kill a few cells but the majority survive, and the immune system stays strong. “That’s the evolutionary solution—not to control the virus but to control the host response,” says Greene. “I think if we had another million years, we’d evolve in the same way.” Thankfully, his team is working to a tighter schedule. They’ve already found a molecule that can stop pyroptosis, at least in lab-grown cells.
The whole messy process depends on a protein called caspase-1. Without it, you don’t get any mature IL1β, and without that, you don’t trigger the vicious cycle of CD4 cell death. Caspase-1 plays many other roles in the body, and several pharmaceutical companies have tried to make drugs that block it, for the purposes of treating other diseases. One of these, VX-765, was developed to treat chronic epilepsy and autoimmune diseases. Greene’s team showed that it completely prevents HIV from killing the bystander CD4 cells. No caspase-1 activity. No IL1β signals. No inflammation. No mass cell death. No AIDS? That remains to be seen. These are only lab experiments, after all, and the drug still needs to be tested in actual HIV patients.
The Dish 