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4/2/97
IN THESE T CELLS, HIV DOES NO HARM
STANFORD -- Researchers have identified certain T cells that suppress the reproduction of HIV carried within them.
These cells, called naive CD4 T cells, mount the body's initial response to infections such as HIV, the virus that causes AIDS. About half of all CD4 T cells circulating in a healthy adult are "naive."
The finding that HIV can't replicate in these cells -- and as a result can't directly harm them -- could lead to new weapons against HIV, said Mario Roederer, a genetics research associate at Stanford University School of Medicine. It also adds to the evidence that something other than viral infection destroys HIV patients' T cells.
"Until now, many researchers believed that the CD4 T cells disappear because HIV gets into them and kills them. But since HIV doesn't kill naive T cells, something else must be causing the loss of these cells in people with HIV disease," said Roederer, lead author of a paper describing the finding in the April issue of the Journal of Clinical Investigation.
"Our current theory is that it's the destruction of the thymus that is causing the abnormally low levels of T cells. But we don't really know," he said.
The thymus is a chestnut-sized gland at the base of the throat. All T cells originate in the bone marrow and then migrate to the thymus, where they are "taught" to recognize foreign molecules, or antigens. The thymus then releases the T cells into the bloodstream, where they lie in wait to intercept invaders. Because they have not yet encountered an antigen, these cells are called naive.
Once they meet their first foreign molecule, naive T cells initiate an attack, proliferate and turn into specific "memory" T cells, which protect the body against subsequent attack from the same invader.
Two types of T cells -- CD4 and CD8 -- serve as the main actors in the immune system's efforts to seek and destroy foreign molecules.
In 1995 Roederer and colleagues published the first report that patients with HIV had very few naive CD8 T cells. Before that, most researchers thought naive CD8 T cells were unaffected by HIV infection because it was known that HIV couldn't get inside CD8 T cells.
Roederer's report, in the May 1995 Journal of Clinical Investigation, showed that naive CD8 T cells in people with HIV were vanishing, despite the cells' resistance to direct HIV infection. This was one of the first inklings that something other than direct viral infection destroys the T cells in people with HIV disease, Roederer said.
The finding sparked his curiosity about HIV's ability to replicate in different types of T cells.
To evaluate this ability, the researchers had to trigger the T cells to divide, since HIV replicates only minimally in quiescent cells. In test tube studies, they separated HIV- infected naive T cells from HIV-infected memory T cells and got them to divide by exposing them to the body's natural stimulatory proteins.
"What was interesting was that the memory cells produced virus under this stimulation, but the naive cells produced none," Roederer said.
"The virus did not replicate in the naive cells, although the virus was there. The cells divided like mad, but the virus did not come out. That's interesting because it breaks the paradigm of viral replication being tied to cell replication. Now we know there are ways of activating cells which do not activate virus," he said.
"It also means naive cells in some way suppress viral replication. How? If we could figure out how they suppress replication, that could lead to a therapy," Roederer said.
The new finding is bolstered by the results of another recent study showing that HIV replication is impaired in weakly stimulated naive CD4 T cells. In this study, reported in the March issue of the journal Blood by Tom Folks of the Centers for Disease Control and Prevention, researchers stimulated CD4 T cells to divide using a different strategy. They got essentially the same result as Roederer: no HIV replication.
The observation that HIV does not replicate in naive CD4 T cells explains a surprising finding reported in the June 28, 1996, Science, Roederer said. In that study, led by Carl June of the Naval Medical Research Institute in Bethesda, Md., researchers triggered HIV-infected CD4 T cells -- both naive and memory types -- to divide repeatedly, increasing in number one millionfold.
After these divisions, the researchers found no virus left in the culture. "It's as if the culture cured itself of HIV," Roederer said.
Some researchers have suggested using this phenomenon therapeutically. "You could take CD4 T cells from people with HIV and allow the cells to multiply. This would eliminate the virus from their cells. Then you could give them back their own virus-free cells," Roederer said.
His new study suggests an explanation for the disappearance of HIV from CD4 T cell cultures that have gone through many generations of divisions. Roederer said he suspects that the naive cells' ability to proliferate more quickly than memory cells allowed the naive cells to take over the final cell mixture in Carl June's study. And since HIV can't replicate in the naive cells, the amount of virus dwindled to nothing after repeated cell divisions.
Roederer's collaborators in the new work at Stanford were laboratory technician Paul A. Raju, postdoctoral fellow Dipendra K. Mitra, and genetics professors Leonore A. Herzenberg and Leonard A. Herzenberg.
The research was funded in part by the National Cancer Institute and the National Institute of Allergy and Infectious Diseases.
--rs--
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