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Thursday, Oct. 17, 2002

NATURAL SELECTIONS

Searching within ourselves for the vaccine against HIV


It is 2005, in what was formerly the state of California. After a massive earthquake, the golden state has been divided into two: So. Cal and No. Cal. Scrawled and sprayed on walls and wreckage is the name of the people's savior: J.D. Shapely.

The scenario is from William Gibson's 1993 novel, "Virtual Light." Shapely is variously held up as a martyr, messiah or folk hero because in his genes was found the vaccine against HIV and the cure for AIDS.

Gibson is the writer who anticipated the influence of the Internet long before most people had even heard of it and before it even existed in the form it does today: He coined the term "cyberspace" to describe it (in his 1984 novel, "Neuromancer").

Many scientists suspect that Gibson's predictions for a cure for AIDS will be borne out, just as his predictions for cyberspace are starting to come true. And a paper published in November's issue of Nature Immunology suggests that he was on the right track about AIDS.

It has been known for some time that there are certain people who can control the spread of HIV within their body and who do not develop AIDS, even after being HIV positive for up to 20 years. These rare people are called nonprogressors. Nonprogressors interest researchers because, like Shapely, their immune systems may contain the potential vaccine and cure for AIDS, which affects 40 million people worldwide and has killed 25 million.

It was long thought by scientists (and is still believed by most of the public) that people succumbed to HIV because they couldn't produce enough of what are called T-cells, vital cells required by the immune system to fight the virus. However, the new study suggests that it is not the number but the quality of a certain class of T-cell, CD8+ T-cells, that is important. The study, of 40 people with HIV, including 15 nonprogressors, showed that both types of patient had about the same number of CD8+ T-cells, but that those of nonprogressors functioned better than in those patients whose virus was spreading.

T-cells belong to a family of white blood cells called lymphocytes. There are two main subsets of T-cells, identified by structures on the cell surface called clusters of differentiation (CD). CD4+ T-cells are known as "helper" T-cells, and CD8+ T-cells are the critical "killer" T-cells. CD4+ T-cells help coordinate the body's immune response and CD8+ T-cells identify cells that have been infected with the virus -- and destroy them.

T-cells are produced, at a rate of about 6 billion a day, for instance, in 20-year-olds, in the thymus gland, which is just behind the breastbone. Once they have been assigned a target by the immune system, T-cells set off on a search-and-destroy mission, to locate and eliminate any infected cells and limit the ability of the virus to reproduce. To perform this task, CD8+ T-cells release a chemical called perforin that kills off cells infected with HIV.

"Some of the newer techniques used in this study enabled us to see the functional differences in the CD8+ T-cells of the two groups," said Stephen Migueles, of the National Institute of Allergy and Infectious Diseases in Bethesda, Md., and the lead author of the Nature immunology paper.

In other words, CD8+ T-cells of the lucky nonprogressors are better at resisting HIV infection. But CD8+ T-cells do not attack HIV directly. They target their own kind: immune-system cells that are infected with HIV.

"For some time we have known that even patients who cannot control HIV maintain high numbers of HIV-specific CD8+ T-cells," said Mark Connors, of NIAID's Laboratory of Immunoregulation, and a coauthor of the paper. "It's a mechanism that tells us a little bit more about how HIV evades controls and how that might be reversed. This study is the first time our lab has been able to find some property within the CD8+ T-cell . . . that is different in these individuals [nonprogressors]."

The paper is particularly important to researchers trying to find a vaccine for HIV, a goal that is more urgent than ever. South Africa alone has 13 percent of the world's population of HIV-positive people and 1.2 million children there have been orphaned as a result of HIV/AIDS. Most children are infected in the womb by their mothers. In sub-Saharan Africa 470,000 children die every year from AIDS.

Many ideas have been tried, but none have yet worked well. For more than a decade, the immune-based therapy interleukin-2 and the therapeutic vaccine Remune have been used in clinical trials, with little in the way of a breakthrough. The new finding about CD8+ T-cells and perforin might open up new lines of research to produce vaccines that improve the function of CD8+ T-cells in HIV-positive people, and so slow and control the rate of HIV proliferation, Connors said.

Everyone knows there is still a long way to go, but our understanding of how the incredibly complex immune system operates is increasing exponentially. Connors and the NIAID team plan to analyze an even broader array of differences between CD8+ T-cells of nonprogressors and those infected with HIV in order to find out what causes the poor functioning of CD8+ T-cells in most of the human population, those not fortunate enough -- like the real-life J.D. Shapelys -- to have a natural immunity to HIV proliferation.

E-mail Rowan Hooper at rowhoop@gol.com


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