New Clue in HIV Mystery
Immune-Cell Factor May be Why Some People With HIV Never Develop
Editorial Note: In the Jan. 23, 2004, issue of Science, Ho and
colleagues retract "an interpretation" made in their September 2002
Ho's original paper said that molecules called alpha defensins are the
long-sought CAF -- CD8 antiviral factor. Indeed, these molecules do have
anti-HIV activity. But now Ho says he was wrong about where they come from. The
alpha defensins don't come from CD8 T cells at all, he says. Instead, they
"leaked" from another kind of immune cell into the CD8 cells during
Sept. 27, 2002 -- It's the central mystery of AIDS: Why do a
very few people with HIV infection never get sick? Now one of the biggest names
in AIDS research says he has the answer.
The breakthrough -- if, indeed, it proves to be one -- comes
from the lab of David D. Ho, MD, at New York's Aaron Diamond AIDS Research
Center. Ho's team used a brand-new tool that can identify incredibly small
amounts of substances produced by human cells.
The researchers also have another prized research tool -- a
group of men who've had HIV infection for many years and remain completely
healthy despite never having taken any anti-HIV drugs. These men's immune cells
make a mysterious factor -- CAF -- that neutralizes HIV. What is CAF? That
question has stumped scientists since 1986. There have been lots of candidates,
but no winners.
Now Ho's group says CAF is unmasked. The suspects: three
specific types of germ-killing molecules called alpha-defensins. These tiny
proteins are made by different cells of the immune system. Defensins are known
to kill bacteria, and they are also known to inactivate HIV, herpes viruses,
and flu virus. Earlier studies of defensins showed they were too weak to be the
long-sought CAF. But Ho's team says that the alpha-defensins they've isolated
appear to be much more potent.
"Additional studies are necessary to define the true
antiviral potency of alpha-defensins, which in turn will determine their
clinical utility in treating HIV," Ho and colleagues write.
Not everyone believes the findings. Jay Levy, MD, PhD, of the
University of California, San Francisco, in 1986 identified CAF as a factor
made by immune cells called CD8+ lymphocytes. These cells are known to be
essential for fighting HIV. CAF has the near-magical property of inactivating
HIV without killing cells infected by the virus. But after years of effort,
Levy still hasn't found CAF. He says Ho hasn't either. Levy told Science
reporter Jon Cohen that his lab has tested defensins and ruled them out.
Another of the biggest names in AIDS research -- HIV
co-discoverer Robert Gallo, MD -- has also looked for CAF. Years ago he claimed
that the majority of the effect was due to another immune-cell substance --
beta chemokines. Yet further study showed that beta chemokines couldn't
inactivate all forms of HIV. CAF can. Gallo now says that there is no such
thing as CAF, Cohen reports. Instead, he says, immune cells make many
substances that together have the long-sought CAF activity. And Gallo hints
that his lab has found an as-yet-unveiled immune factor that is far more
powerful than defensins.