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Research Highlights
VA-NYU Scientist Leads $8.4-million Effort Toward AIDS Vaccine
September 21, 2006
This article was taken from VA Research Currents, September 2006.
Susan Zolla-Pazner, PhD, of the VA New York Harbor Healthcare System and New York University, will lead an international team of scientists in a new multimillion-dollar project aimed at developing vaccines against the AIDS virus.
Zolla-Pazner will direct the NYU AIDS Vaccine Discovery Consortium, which has received $8.4 million over three years from the Bill and Melinda Gates Foundation. The project is among others worldwide funded by Gates as part of its Collaboration for AIDS Vaccine Discovery.
The consortium will involve specialists in immunology, virology, crystallography, and structural and computational biology. Zolla-Pazner's team, representing four U.S. sites and four in India and Cameroon, plans to isolate the most powerful antibodies found in patients infected with various HIV strains. They will then identify structures on the virus surface that are targeted by these antibodies, and incorporate them into genetically engineered vaccines that will be tested in rabbits.
One structure to be targeted is the socalled
"V3 loop" on HIV's protein coating,
which is known as gp120.
"The Gates Foundation grant will enable
us to develop candidate vaccines that focus
the immune response on the V3 loop of the
gp120 protein," said Zolla-Pazner. "This is
a proof-of-principle project. If it succeeds, it
could be extended to the study of other parts
of the HIV virus as well as to other diseasecausing
organisms."
In the past, many scientists hoped gp120
would provide the basis for successful vaccines
because the immune system produces
antibodies against it. But a large clinical
trial of a vaccine based on this strategy
failed, and some researchers lost hope that
the antibody approach would work.
Zolla-Pazner, however, has continued
since the early 1980s to study pieces of the
proteins enveloping the HIV virus, and the
antibodies elicited by these foreign strands.
She said the V3 loop has remained especially
promising. HIV uses this structure to gain
a foothold on cells of the immune system.
During infection, the V3 loop remains at
least partially exposed to the immune system
and produces strong antibodies. Unlike
others that have proved more problematic,
these antibodies don't react with any of the
body's own proteins.
"At one time, everybody thought that
making antibodies to V3 was the way to
prevent HIV infection and that this was
going to be a slam dunk," said Zolla-Pazner.
But research in mice suggested that anti-
V3 antibodies could recognize only a few
strains of HIV, and many scientists abandoned
this path.
"Our data showed that they weren’t as
specific as everybody else thought," said the
VA researcher. "We had found an antibody
to V3 that was really interesting and had the
ability to block the infection of lots of HIV
strains."
The V in V3 stands for variable. The
loop is made of sequences of amino acids
that vary widely according to the strain
of HIV. Only a handful of the sequences
are the same in infected individuals, and
there are thousands of sequences. Using
crystallography and structural biology,
Zolla-Pazner and colleagues have begun to
understand how the varying V3 loops are
recognized by neutralizing antibodies, and
how these antibodies prevent HIV from
infecting cells.
One of the V3’s hallmarks is a hairpin-like turn. Even though the amino acid
sequences of the loop vary, its fundamental
structure remains the same. "The V3 region
in different viruses is indeed always changing
but its shape is always similar," said
Zolla-Pazner. She explained that antibodies
recognize the common features of the V3
loop in the same way our eyes identify faces
by the position of the eyes,
nose, and mouth.
Her lab has already
isolated powerful
neutralizing
antibodies
from
the blood
of patients
infected
with HIV
subtype B,
most common mon
in Europe and the U.S. Her colleagues
plan to collect blood from HIV-positive
volunteers in Cameroon and India so they
can cull additional antibodies from those
infected with subtypes A and C, which
predominate in those areas. Subtypes A, B,
and C account for about 86 percent of all
HIV strains.
The antibodies will be tested for neutralizing
activity and the most broadly acting
will be "crystallized" along with the V3
loops they recognize. The crystals will provide
the basis for molecular modeling studies
that will analyze the atomic structure
of the V3 loop and its associated antibodies.
The models will help the researchers
identify the features of the V3 loop that
are eliciting the antibodies, and help them
design vaccines accordingly.
Zolla-Pazner also heads a VA Research
Enhancement Award Program (REAP),
established in 2002 to spearhead work in
designing and developing vaccines for
AIDS, tuberculosis and other infectious
diseases.
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