New vulnerability found in HIV virus gives potential for new vaccine
24 April 2014
A new vulnerable site on the HIV virus that doesn't mutate or
vary between strains has been identified by a team led by scientists
at The Scripps Research Institute (TSRI) working with the
International AIDS Vaccine Initiative (IAVI). The new site can be
attacked by human antibodies in a way that neutralizes the
infectivity of a wide variety of HIV strains.
The discovery is part of a large, IAVI- and NIH-sponsored effort
to develop an effective vaccine against HIV. Such a vaccine would
work by eliciting a strong and long-lasting immune response against
vulnerable conserved sites on the virus — sites that don’t vary much
from strain to strain, and that, when grabbed by an antibody, leave
the virus unable to infect cells.
HIV generally conceals these vulnerable conserved sites under a
dense layer of difficult-to-grasp sugars and fast-mutating parts of
the virus surface. Much of the human body's antibody response to
infection is directed against the fast-mutating parts and thus is
only transiently effective.
The findings were reported in two papers appearing in the May
issue of the journal Immunity.
“HIV has very few known sites of vulnerability, but in this work
we’ve described a new one, and we expect it will be useful in
developing a vaccine,” said Dennis R. Burton, professor in TSRI’s
Department of Immunology and Microbial Science and scientific
director of the IAVI Neutralizing Antibody Center (NAC) and of the
National Institutes of Health’s Center for HIV/AIDS Vaccine
Immunology and Immunogen Discovery (CHAVI-ID) on TSRI’s La Jolla
“It’s very exciting that we’re still finding new vulnerable sites
on this virus,” said Ian A. Wilson, Hansen Professor of Structural
Biology, chair of the Department of Integrative Structural and
Computational Biology and member of the Skaggs Institute for
Chemical Biology at TSRI and member of the NAC and CHAVI-ID.
Prior to the new findings, scientists had been able to identify
only a few different sets of “broadly neutralizing” antibodies,
capable of reaching four conserved vulnerable sites on the virus.
All these sites are on HIV’s only exposed surface antigen, the
flower-like envelope (Env) protein (gp140) that sprouts from the
viral membrane and is designed to grab and penetrate host cells.
An electron microscopic reconstruction of the
HIV-1 envelope glycoprotein trimer (pale blue) with antibodies
representing each site of vulnerability in different colours,
including the newly discovered PGT151 shown in red. (Image by
Christina Corbaci, courtesy of The Scripps Research Institute.)
The identification of the new vulnerable site on the virus began
with tests of blood samples from IAVI Protocol G, in which IAVI and
its NAC partnered with clinical research centres in Africa, India,
Thailand, Australia, the United Kingdom and the United States to
collect blood samples from more than 1,800 healthy, HIV-positive
volunteers to look for rare, broadly neutralizing antibodies.
The serum from a small set of the samples indeed turned out to
block the infectivity, in test cells, of a wide range of HIV
isolates, suggesting the presence of broadly neutralizing
antibodies. In 2009, scientists from IAVI, TSRI and Theraclone
Sciences succeeded in isolating and characterizing the first new
broadly neutralizing antibodies to HIV seen in a decade.
Emilia Falkowska, a research associate in the Burton laboratory
who was a key author of the first paper, and colleagues soon found a
set of eight closely related antibodies that accounted for most of
one of the sample’s HIV neutralizing activity. The scientists
determined that the two broadest neutralizers among these
antibodies, PGT151 and PGT152, could block the infectivity of about
two-thirds of a large panel of HIV strains found in patients
Curiously, despite their broad neutralizing ability, these
antibodies did not bind to any previously described vulnerable
sites, or epitopes, on Env — and indeed failed to bind tightly
anywhere on purified copies of gp120 or gp41, the two protein
subunits of Env. Most previously described broadly neutralizing HIV
antibodies bind to one or the other Env subunit. The researchers
eventually determined, however, that PGT151 and PGT152 attach not
just to gp120 or gp41 but to bits of both.
In fact, gp120 and gp41 assemble into an Env structure not as one
gp120-gp41 combination but as three intertwined ones — a trimer, in
biologists’ parlance. PGT151 and 152 (which are nearly identical)
turned out to have a binding site that occurs only on this mature
and properly assembled Env trimer structure.
“These are the first HIV neutralizing antibodies we’ve found that
unequivocally distinguish mature Env trimer from all other forms of
Env,” said Falkowska. “That’s important because this is the form of
Env that the virus uses to infect cells.”