January 15, 1999
New AIDS Vaccine Approach Aims to Catch Virus in the Act
A novel approach to producing antibodies
against the AIDS virus has proven effective against a wide range of HIV
strains, raising the hope that a broadly effective vaccine is possible. The
new approach generates immune system antibodies against the infective
proteins of the virus while the virus is fusing with a target cell.
Scientists from the University of Montana and the Howard Hughes Medical
Institute (HHMI) at New York University Medical Center sought to "freeze"
the AIDS viral machinery in the act of contorting itself to fuse with its
target cell. The investigators believed that this transition stage in the
infective process exposes immune-triggering molecules that the virus
normally keeps hidden within the depths of its structure.
“This is really the first example of being able to somehow trick the immune system into making broadly neutralizing antibodies that are presumably active against the HIV envelope glycoprotein.”
Dan R. Littman
The scientists' success at producing broadly effective antibodies against
HIV is in sharp contrast to previous efforts, in which the resulting
antibodies neutralized laboratory-grown HIV strains, but not "primary
isolates," strains of the virus found in AIDS patients.
Reporting the new findings in the January 15, 1999, issue of the journal
Science
are University of Montana researchers Jack Nunberg, Rachel
LaCasse, Kathryn Follis and Meg Trahey; and
Dan Littman
and
John Scarborough of HHMI at New York University Medical Center.
"Perhaps to the surprise of all involved, this ambitious experiment
worked," wrote AIDS researchers David Montefiori and John Moore in a
commentary on this work that was also published in the January 15 issue of
Science
. "The mouse sera, and antibodies purified from them, inhibited the infectivity of an impressive array of
diverse HIV-1 primary isolates, including viruses from multiple genetic
subtypes." Montefiori is at Duke University Medical Center, and Moore is at
The Rockefeller University.
Nunberg and his colleagues began by constructing a molecular facsimile of
the AIDS infective machinery and of the receptors to which it binds on
surface of host cells.
They first genetically engineered monkey cells to produce the HIV
surface, or envelope, molecules that are responsible for grabbing onto human
cells in the infective process. These surface molecules are called
glycoproteins. The researchers then mixed these monkey cells with human
cells whose surface was festooned with the receptors that HIV latches onto
in infecting cells.
The scientists "froze" the combined cells in the act of fusing by
treating them with a weak solution of formaldehyde, which forged a web of
chemical links that trapped the molecules in place.
The researchers then injected this mixture, which they dubbed a
"fusion-competent immunogen," into mice that Littman's team had genetically
engineered to also produce the human receptors. Littman's group had
developed the mice specifically to serve as models for HIV vaccine
development. Using such mice for immunization was necessary to avoid having
the animals' immune system react to the foreign human receptors, rather than
to the HIV machinery.
Finally, the Montana scientists isolated an antibody-rich blood serum
from the immunized mice. They tested this serum's effectiveness against HIV
by mixing it with a diverse collection of viruses isolated from infected
humans. The researchers discovered that the antibodies effectively
neutralized every one of the many different strains of HIV.
"I think it's a very, very encouraging development," says Littman. "Until
now, it has been very difficult to generate antibodies against HIV envelope
glycoprotein that are broadly reactive. This is really the first example of
being able to somehow trick the immune system into making broadly
neutralizing antibodies that are presumably active against the HIV envelope
glycoprotein."
Nunberg, Littman and their colleagues emphasize that while the new
approach is highly promising, much work remains for the method to prove
useful in a vaccine for humans. For one thing, they said, injection of whole
live cells into humans is not practical in terms of vaccine safety or
durability.
Rather, said Littman, a vaccine will likely depend on isolating the
specific glycoprotein that triggers response to HIV and producing it using
recombinant DNA technology. "Based on this advance, however, I think there
is a good possibility that we'll be able to mimic the immunogenic properties
of fusion-competent envelopes on cells by instead using recombinant
proteins," he said.
The scientists also said it will be important to determine whether the
antibodies they generated in mice can also be generated in primates and,
eventually, in humans.
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