Newsday - Tuesday, June 6, 2001
Laurie Garrett, Staff Writer

Twenty years later scientists still don't know what kills the cells. And its eventual discovery will be key to understanding AIDS - defined as a rise in the numbers of viruses in the bloodstream coupled with a fall in the CD4 cell count. The U.S. Centers for Disease Control and Prevention's defining line is a CD4 count below 200 cells per milliliter of blood. (Normal CD4 levels are 1,000 and above.) The CD4 cells are one element in the immune system's constellation of cells and chemicals. In an orchestrated manner, each must execute its role in response to a perceived threat of microbial invasion.

The job of the CD4 cells is to help link the rest of the system, directing antibodies and other fighter cells to a target. For this reason, CD4s are also called helper lymphocytes.

Loss of these helper cells makes the immune system go into disarray: The orchestra ceases playing in harmony. That cacophony leaves the body defenseless against other invaders. If scientists could explain why the CD4 cells die, they would be on course to find a way to arrest that fatal process.

"It's actually a matter of some debate what makes these cells die so rapidly," Tufts University molecular biologist John Coffin said. It is "the fundamental question: why CD4 cells die." These helper cells are the primary targets of the virus: To infect one, HIV must latch on to a protein that protrudes from the cell's membrane, called the CD4 receptor. The virus then moves in, makes copies of itself and extrudes millions more new viruses every day. But since it is not in HIV's interests to kill off its "home" cell, most scientists believe a complex interaction is at play, causing the cells' deaths.

In the mid-1990s several laboratories, notably that of Dr. David Ho, director of the Aaron Diamond AIDS Research Center in Manhattan, developed mathematical models of the disease that correlated CD4 die-offs with rising HIV levels. They reasoned that regardless of how the CD4 cells were dying, loss of immune system function was a result of rising HIV levels. And then, with the use of highly active antiretroviral therapy (HAART) drugs, their models showed that viral loads went down, CD4 levels came back up and eventually all the AIDS viruses in a patient's body would be eradicated. Ho and others assumed that CD4 cells were normally short-lived, so a few years of HAART would eliminate all the HIV "homes." Now, however, it is known that some cells can be latently infected with HIV for decades, which means HAART will never be able to eliminate all vestiges of HIV from a patient.

"These are like embers that are left behind in a fire. If the fire department leaves too soon, the embers can start the fire right back up again," Coffin explained. Researchers say millions of new CD4 cells are made every day in the bodies of infected patients, replenishing those that have died. But billions of new viruses are also made, eventually far outpacing CD4 cell production.

"The system remains in an extraordinarily robust quasi-steady state for thousands of cycles before progressing to diseases," Coffin continued. "But it always goes slowly downhill, at least in humans. And we still don't know what causes infections to progress to disease." For Ho, finding an answer to that question has become a personal challenge.

Because of his role in developing the 1990s model for HIV / CD4 interactions and promoting use of HAART, Ho was named Time Magazine's Man of the Year for 1996. But when the bubble of hope for HIV eradication burst, with recognition of these latent, infected CD4 cells, Ho came under criticism - so much so that today he rues ever having been honored.

"I try to be a good guy in the field, but it's quite a shock to get hate mail, and to have a lot of people who want to take you down a notch or two," he said in a recent interview.

So for five years Ho's lab has been trying to figure out what kills CD4 cells.

In monkey studies, using the simian immunodeficiency virus or SIV, the lab has measured increases in CD4 cell production up to six times more in response to SIV, compared to normal production. Yet the die-off rate also increases and eventually outpaces production, so that overall CD4 counts plummet.

"Mechanistically, we don't know what's doing it, but the higher the viral replication rate, the greater the cell turnover," Ho said, suggesting that the virus may be secreting factors that actively promote the body's production of more would-be "homes" for SIV or HIV.

Dr. Bruce Patterson of Children's Memorial Hospital in Tucson, Ariz., has unpublished evidence that HIV prompts some of these infected helper cells to shed their CD4 receptors. Patterson concludes that many of the cells aren't dead but instead have been corralled into use by the viruses and hidden from detection through shedding of their receptors.

Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, said that may be just one of several factors involved in the disappearance of CD4 cells, including apoptosis (or cellular suicide), malfunctions in chemical signaling mechanisms and homicidal immune system cells that think these infected CD4s are enemies. The latter, Fauci said, may be the most profound, as infected cells may carry proteins derived from HIV. So CD4 helper cells are, at least in part, victims of friendly fire from their own immune system troops.

Finally, there is substantial evidence that HIV infection leads to a sloppy buildup of viral products inside CD4 cells. Human cells have a janitorial service meant to clean up such messes, called the ubiquitin-proteosome system.

HIV secretes substances that block ubiquitin, so the garbage just keeps piling up. The cell's eventual response is suicide.
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