MADISON, Wis. -- Scientists may want to rethink the current theory that to be effective, vaccines must completely eliminate an invading virus. Researchers at the University of Wisconsin Medical School have shown that vaccination can reduce or prevent fatal immune responses to a virus in mice, even though the virus continues to live in the animals.
Reported in the current issue of the journal Vaccine, the findings may have important implications for treating AIDS, herpes and other viral infections.
"The common thinking with such infections is that we must completely erase the virus in order for an organism to survive and be protected from disease," said Dr. Daniel Muller, UW Medical School assistant professor of medicine and medical microbiology and immunology. "But for viruses that cause chronic or latent infections, reducing or preventing the development of symptoms may be enough."
Muller and his team studied normal and immune-deficient mice they infected with LCMV, a virus that by itself won't kill the animals but stimulates an extreme immune response leading to fatal meningitis. Such a response, known as immune pathology, often is what kills an organism.
"Immune pathology is like a bystander effect," said Muller. "As the immune system tries to get rid of a foreign invader, it may cause widespread damage in the process."
Normal mice responded to LCMV by producing immune cells called CD8 cytotoxic T cells, which attack virus-infected or malignant cells, resulting in the lethal meningitis. To the researchers surprise, the immune-deficient mice, which do not have CD8 cytotoxic T cells, produced weaker immune cells, CD4 cytotoxic T cells. For some reason, CD4 cells yielded less severe meningitis with fewer deaths, although many of the mice experienced significant weight loss.
The UW team next vaccinated the mice against LCMV. The vaccine prevented meningitis in the normal mice and eliminated the virus. In the immune-deficient mice, known to be susceptible to meningitis, vaccination prevented disease and death in a majority of the mice, but not severe weight loss. Although these mice did not die, they were unable to clear the virus from their brains or spleens, probably because the CD4 cells did not work as effectively as CD8 cells, said Muller.
"Although meningitis is an acute disease, what we have shown here may be a good model for vaccination against persistent infections such as AIDS, herpes zoster and tuberculosis," he said. "If it is proven that the destructive events that occur in HIV infection are due primarily to immune pathology, we may be able to use vaccination to decrease this pathology without having to get rid of the infection."
Studies in which kittens were vaccinated against feline leukemia virus and monkeys against simian immunodeficiency virus infection have shown that vaccines can prevent or delay development of disease without eliminating the virus, he added.
The UW research builds on earlier work that won Peter Doherty and Rolf Zinkernagel this year's Nobel Prize in Physiology or Medicine. They before cytotoxic T cells can kill a virus-infected cell, they must recognize both a piece of the virus and a special immune protein that identifies the individual organism.
Muller's previous research, reported in the journal Science, showed that if CD8 cytotoxic T cells are removed, they will be replaced by CD4 cytotoxic T cells.
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