MINNEAPOLIS / ST. PAUL--In a finding that uncovers a new obstacle to preventing or eradicating AIDS, researchers at the University of Minnesota and seven other institutions have found that HIV-1, which is usually transmitted by heterosexual contact, infects and replicates in immune cells whose relative inactivity puts them beyond the reach of current therapies. The study will be published in the Nov. 12 issue of Science.
Previously, scientists thought that HIV could not reproduce itself inside T cells, the major targets of the virus, unless the cells had been activated, said Ashley Haase, Regents Professor of Microbiology at the University of Minnesota and corresponding author of the study. Activation occurs when a T cell encounters a molecule, usually a protein or protein fragment, that signals potential danger and starts the cell on a course that leads to rapid cell reproduction. If the T cell is infected with HIV, the virus takes advantage of the activity by commandeering the cell's reproductive machinery and churning out many copies of the virus, which can then infect other T cells. This cellular piracy kills the T cells.
On the other hand, said Haase, T cells that have not been activated ("resting" T cells) were thought to provide little or no opportunity for the virus to replicate and spread. The theory was that the virus first infected other white blood cells known as macrophages and dendritic cells, and these later passed the infection to activated T cells. But studies spearheaded by Zhi-Qiang Zhang, a research associate in Haase's department, showed otherwise. In monkeys infected with SIV (the simian form of the virus), viral particles were detectable mainly in T cells as early as three days after infection--the earliest it was found in macrophages and dendritic cells. Thus, said Haase, the study provides no support for the idea that macrophages and dendritic cells are infected first.
Also at three days post-infection, SIV was found in both activated and resting T cells, and between three and 12 days of infection it expanded faster in the population of resting T cells. Studies with HIV-1 patients showed patterns consistent with this. In the early stages of infection, the distribution of virus in patients' white cells was about 50-50 in resting T cells versus activated cells and at this and all subsequent stages of infection, close to 90 percent of the infected cells were T cells. In the late stages of HIV-1, at least 75 percent of the infection appears in activated T cells, said Haase.
"We think chronically infected cells that produce only a little virus, as well as latently infected resting cells with silent infections, are difficult targets for the immune system or therapy," he said. "These cells fly below the radar screen of the immune system. They also live a long time and won't be affected by our current combinations of anti-AIDS drugs that work by interfering with the chain of new infections that maintains virus production."
Many years of studies with cells in culture led to the belief that resting T cells could not support viral replication, said Haase. Evidently though, he said, there is a difference between resting cells in culture and in the body. "We don't believe a T cell can be truly resting in the body," he said. "In mice, T cells die without stimulation by cells or the proper fluid-borne chemicals. We speculate that contact with such chemicals, known as cytokines, or certain proteins keeps T cells active in some way different from what you see in tissue culture.
"This study identifies a source of cells that are invulnerable to current therapies." A vaccine will also be hard to develop, he said, because cytotoxic T cells, the normal destroyers of foreign material, kill foreign material by recognizing and killing activated T cells in which the material--such as HIV--is reproducing itself. "Resting" T cells are left alone. Activated, HIV-positive T cells mark themselves for destruction by displaying fragments of the virus on their outer surfaces. The "resting" infected cells display much less or none at all.
"I think the immune system wasn't designed to function with low levels of infection," said Haase. "There just aren't handles for the cytotoxic T cells to find, especially where so many T cells are activated and clamoring for attention."
In addition to the University of Minnesota, the study was carried out by researchers at Beth Israel Deaconess Medical Center, Boston; the University of Pittsburgh; the California Regional Primate Research Center, Davis; the University of Amsterdam Academic Medical Centre, the Netherlands; the University of California, San Diego; the Bernhard-Nocht Institute for Tropical Medicine, Hamburg, Germany; and Northwestern University Medical School, Chicago.
Contacts:
Ashley Haase, microbiology dept., 612-624-4442
Deane Morrison, University News Service, 612-624-2346
Journal
Science