In These T Cells, HIV Does No Harm

Researchers have identified certain T cells that suppress the reproductionof HIV carried within them. These cells, called naive CD4 T cells, mountthe body's initial response to infections such as HIV. About half of allCD4 T cells circulating in a healthy adult are "naive."

The finding that HIV cannot replicate in these cells-and as a resultcannot directly harm them-could lead to new weapons against HIV, said MarioRoederer, a genetics research associate at Stanford University School ofMedicine. It also adds to the evidence that something other than viralinfection destroys HIV patients' T cells.

"Until now, many researchers believed that the CD4 T cells disappearbecause HIV gets into them and kills them. But since HIV does not killnaive T cells, something else must be causing the loss of these cells inpeople with HIV disease," said Roederer, lead author of a paper describingthe finding in the April issue of the Journal of Clinical Investigation.

"Our current theory is that it's the destruction of the thymusthat is causing the abnormally low levels of T cells. But we don't reallyknow," he said.

The thymus is a chestnut-sized gland at the base of the throat. AllT cells originate in the bone marrow and then migrate to the thymus, wherethey are "taught" to recognize foreign molecules, or antigens.The thymus then releases the T cells into the bloodstream, where they liein wait to intercept invaders. Because they have not yet encountered anantigen, these cells are called naive.

Once they meet their first foreign molecule, naive T cells initiatean 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 immunesystem's efforts to seek and destroy foreign molecules.

In 1995 Roederer and colleagues published the first report that patientswith HIV had very few naive CD8 T cells. Before that, most researchersthought naive CD8 T cells were unaffected by HIV infection because it wasknown 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, despitethe cells' resistance to direct HIV infection. This was one of the firstinklings that something other than direct viral infection destroys theT cells in people with HIV disease, Roederer said. The finding sparkedhis curiosity about HIV's ability to replicate in different types of Tcells.

To evaluate this ability, the researchers had to trigger the T cellsto divide, since HIV replicates only minimally in quiescent cells. In testtube studies, they separated HIV-infected naive T cells from HIV-infectedmemory T cells and got them to divide by exposing them to the body's naturalstimulatory proteins.

"What was interesting was that the memory cells produced virusunder this stimulation, but the naive cells produced none," Roederersaid. "The virus did not replicate in the naive cells, although thevirus was there. The cells divided like mad, but the virus did not comeout. That's interesting because it breaks the paradigm of viral replicationbeing tied to cell replication. Now we know there are ways of activatingcells which do not activate virus," he continued. "It also meansnaive cells in some way suppress viral replication. How? If we could figureout how they suppress replication, that could lead to a therapy,"Roederer said.

Support From Another Study

The new finding is bolstered by the results of another recent studyshowing that HIV replication is impaired in weakly stimulated naive CD4T cells. In this study, reported in the March issue of the journal Bloodby Tom Folks of the Centers for Disease Control and Prevention, researchersstimulated CD4 T cells to divide using a different strategy. They got essentiallythe same result as Roederer: no HIV replication.

The observation that HIV does not replicate in naive CD4 T cells explainsa surprising finding reported in the June 28, 1996, Science, Roederersaid. In that study, led by Carl June of the Naval Medical Research Institutein Bethesda, Maryland, researchers triggered HIV-infected CD4 T cells-bothnaive and memory types-to divide repeatedly, increasing in number one million-fold.

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 thecells to multiply. This would eliminate the virus from their cells. Thenyou could give them back their own virus-free cells," Roederer said.His new study suggests an explanation for the disappearance of HIV fromCD4 T cell cultures that have gone through many generations of divisions.Roederer said he suspects that the naive cells' ability to proliferatemore quickly than memory cells allowed the naive cells to take over thefinal cell mixture in Carl June's study. And since HIV cannot replicatein the naive cells, the amount of virus dwindled to nothing after repeatedcell divisions.

The research was funded in part by the National Cancer Institute andthe National Institute of Allergy and Infectious Diseases.