Master of microevolution  pg. 4

“I don’t know why, but everything lined up the right way, and the virus was suppressed to low levels early, before it could do much damage,” Kalams says. “We think that helper responses were preserved and they have great (cytotoxic) T cell responses and they’re maintaining control.”

Thanks to fluorescence-activated cell sorting, Kalams and his colleagues can separate—and study—distinct populations of T cells based on their tendency to proliferate and the fluorescent labels that have been attached to them. “What sort of receptors do they have? How well do they bind (to infected cells)? I’m trying to find the characteristics of each of these cells to see which ones might be the most effective at suppressing HIV replication,” he says.

Recognition of the importance of cellular immunity has led to a new avenue of vaccine development—boosting cytotoxic T cell responses. In vaccine studies in animals, these responses do not prevent HIV from infecting cells, but they can slow down the course of the disease. “It is likely that a successful HIV vaccine will have to elicit both antibody and cellular immune responses,” Kalams says.

Toward that end, Merck & Co., one of the world’s leading vaccine manufacturers, is testing a circular bit of DNA called a “plasmid” that contains a viral gene. The plasmids are injected into muscle. Infected muscle cells are engulfed by the body’s border guards, which transcribe and translate the genetic material into pieces of viral protein. The hope is that these antigens will activate cytotoxic T cells to attack HIV-infected cells.

A multi-pronged attack

At the National Institutes of Health, the Vaccine Research Center is developing a two-stage vaccine: a plasmid expressing modified genes that cover about 80 percent of the antigen content of HIV, followed by a booster consisting of the same genes carried in a harmless adenovirus. The genes are carried into cells by the adenovirus where they produce the simulated viral proteins that are processed and presented on their surfaces.

In early studies in animals and uninfected humans, this approach has triggered significant increases in both cytotoxic T cells and helper T cells, says Barney Graham, M.D., chief of the Viral Pathogenesis Laboratory and Clinical Trials Core at the NIH Vaccine Research Center.

Combining a variety of HIV antigens into one vaccine may help prevent the virus from sneaking around the body’s defenses by changing its highly mutable envelope protein. And it may provide protection against different “clades” or species of the virus. Graham hopes the vaccine may be ready for phase III clinical trials, which will measure its ability to reduce or prevent infection in high-risk individuals, by 2006.

HIV’s resilience is due not only to its astounding ability to adapt to its environment. The virus also can hide from the immune system and drug treatment in the DNA of non-dividing T cells. When the cells are activated, years or even decades later, the previously latent virus re-emerges.

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