Biological 'Backfire' May Worsen AIDS

By William J. Cromie

Gazette Staff

When the AIDS virus attacks human cells, the body's powerful immune system immediately starts making proteins called antibodies to fight the invaders. However, these defenses might also kill the same cells they are designed to protect, according to Harvard University researchers.

Antibodies seek out a tiny loop on the surface of the virus and grab on to it. White blood cells spot the union and rush to eliminate the virus. The process is a splendid example of how our natural disease-defense system works.

However, one type of white blood cell, known as T-cells, carry a protein on their surface that resembles the virus loop. Harvard scientists have uncovered strong evidence that antibodies against the AIDS virus can grab these T-cell proteins and cause their destruction.

"The fewer T-cells you have, the harder it is to fight off pneumonia, cancer, and other maladies that cause a virus infection to lead to full-blown AIDS," explains Joseph Brain, Drinker Professor of Environmental Physiology at the Harvard School of Public Health (HSPH). "In other words, the fewer T-cells you have, the sicker you will be. But we don't know for sure what kills T-cells. Some researchers believe that proliferation of the virus in infected T-cells accounts for all the destruction. We believe that misdirected antibody attacks on uninfected T-cells also destroys these cells."

Brain compares the AIDS situation with streptococcus infections that lead to rheumatic heart disease. The body makes antibodies that attack strep bacteria, but these antibodies also go after proteins on heart valves that mimic proteins on the surface of the bacterial invaders.

Brain and Harvard virologist Roberto Trujillo maintain that such molecule mimicry, as it's called, is a more general phenomenon than many medical scientists appreciate. Trujillo has linked this mechanism to AIDS dementia.

"There is compelling evidence that antibodies made in the brain to fight the AIDS virus can cross-react and damage brain cells," Trujillo says.

In fact, his work on dementia led to the research on T-cells. "It made us wonder if the same mimicry mechanism works in different cell types," Brain notes.

Impact on AIDS Vaccines

Trujillo, Brain, and a School of Public Health colleague Rick Rogers published their findings in the June 20 issue of Virology.

The biological backfire they describe has not been conclusively proved, and the researchers do not claim that it is the only cause for T-cell depletion. Nevertheless, the possibility has important implications for vaccines against the human immunodeficiency virus (HIV), which leads to AIDS.

Last month, the Food and Drug Administration approved the first world-scale test of such a vaccine. Called Aidsvax, it is made of a piece of the virus's outer coat, which will stimulate the body to make antibodies.

Part of this piece is the V3 loop that closely resembles the protein attachment point on T-cells. This raises the possibility that some antibodies produced by the vaccine may react with and destroy uninfected T-cells.

"We don't predict this will happen, but we think it's something to be concerned about." Brain warns. "If you were designing a vaccine from scratch, you might want to leave out or modify the V3 region."

That should now be easier to accomplish because another group of Harvard researchers has worked out the three-dimensional structure of HIV and the spiky projections on its surface that allow it to grip white blood cells. Spectacular pictures of how this union takes place were first reveled last month.

To demonstrate what can happen, Trujillo and Brain mixed antibodies against the V3 loop with uninfected human T-cells. They also combined other T-cells with blood from HIV-infected patients, which contains these antibodies. In both cases, 70 percent of the uninfected T-cells died.

Not everyone infected with HIV develops AIDS at the same pace. Brain thinks that the rate of progression is linked to activation of T-cells. HIV activates them, as do other infections. AIDS develops fastest in people who are malnourished and have another type of infection such as a sexually transmitted disease.

"Such activation is required for cells to become susceptible to molecule mimicry," Brain notes. "The greater the activation, the more T-cells are destroyed, and the quicker the disease reaches a life-threatening stage."

What's Next

"We believe that the more V3 antibodies present in blood, and the more V3-like proteins on activated T-cells, the greater the risk for destruction of T-cells," Brain says. "Roberto and I plan to test this idea on banked blood samples taken from those infected with HIV."

Brain and Trujillo will examine blood samples collected over several years from HIV-infected people who varied in the time they took to develop AIDS. By measuring antibody levels and T-cell proteins in these samples, they believe they can predict the amount of T-cell damage and how fast the infection progresses to AIDS. Correct predictions would demonstrate the presence and consequences of molecular mimicry.

To test the idea that antibodies can also attack brain cells and cause AIDS dementia, the researchers are collecting samples of human brain tissue and combining them with HIV. The results may enable them to determine if uninfected cells are killed by antibodies to the virus.

"Many researchers are not convinced that the amount of virus in people with AIDS is large enough to account for the destruction of T-cells that occurs," Brain says. "Our experiments indicate that the body's own immune system may be turning against itself as it does in rheumatic heart disease, rheumatoid arthritis, and other immune diseases. Immunity is a powerful force without which we could not survive. But like 'friendly fire' on a battlefield, it can sometimes disable or kill you."