Revolutionary antibody technology gives hope for vaccine against
genetically diverse HIV
25 September 2009
For the first time an antigen has been created that induces
protective antibodies capable of blocking infection of human cells by
genetically-diverse strains of the human immunodeficiency virus (HIV).
The research was conducted at The University of Texas Health Science
Center at Houston and is published online online in the Journal of
"The complexity of HIV has for long thwarted development of an
effective HIV vaccine. Our findings open a new path toward an effective
preventative and therapeutic vaccine," said Sudhir Paul, PhD, the
study's senior author and a professor in the Department of Pathology and
Laboratory Medicine at The University of Texas Medical School at
"The new antigen is a prototype vaccine. This prototype successfully
eliminates nature's restrictions on the production of
broadly-neutralizing antibodies to HIV by the immune system."
The trial of a vaccine in Thailand that was widely reported worldwide
this week (see end of story) only covered subtype B and E HIV strains that commonly
circulate in Thailand. The subtype B HIV strain is also the one most
commonly found in the United States.
Thirty-three million people were living with HIV at the end of 2007,
according to the World Health Organization. That same year, nearly 3
million people became newly infected, and 2 million died of acquired
immunodeficiency syndrome or AIDS, which occurs at the most advanced
stages of HIV infection.
Vaccines work by introducing an antigen into the body, which spurs
the immune system to produce antibodies that guard against infection.
Previously-tested HIV vaccine candidates stimulated vigorous production
of antibodies to the mutable segments of the virus envelope. But, these
vaccine candidates did not stimulate the production of antibodies to the
regions essential for virus attachment to host T cells, the process that
Scientists in Paul's laboratory used a chemically-activated form of
the HIV envelope protein gp120 to stimulate the production of mouse
monoclonal antibodies that block infection of cultured human cells by
genetically-diverse HIV strains from around the world. Paul said these
same antibodies can be found in humans who remain free of AIDS despite
long-term HIV infection. "HIV infection itself stimulates production of
this class of antibodies, but the amount is too small to control
infection. The challenge is to boost production of the protective
antibodies in humans using a vaccine."
Because of the genetic variability of HIV, most antibodies fail to
stop infection initiated by thousands of different HIV strains
responsible for the pandemic. "Dr Paul's team has developed a
revolutionary antibody technology and used it to overcome major
obstacles to a vaccine for HIV. They identified antibodies that
neutralized 100 percent of strains drawn from the major viral subtypes.
Furthermore, they have developed ways to immunize animals to produce
them. No previous vaccine candidate has even approached these
objectives," said Robert L. Hunter, MD, PhD, professor and chairman of
the Department of Pathology and Laboratory Medicine at the UT Medical
School at Houston.
The vaccine prototype builds on Paul's earlier discovery that a tiny
stretch of amino acids numbered 421-433 in gp120 can serve as the
Achilles heel of HIV.
"Unlike the changeable regions of its envelope, this region must
remain constant to attach to T cells. Equally important, HIV can survive
only if the body's immune system fails to produce antibodies to this
region. The virus minimizes production of antibodies to the vulnerable
region because it also silences B lymphocytes, the cells responsible for
producing antibodies," Paul said.
"In nature, microbial antigens stimulate antibody synthesis when they
bind antibodies on the surface of B cells by weak noncovalent forces. In
the case of HIV, noncovalent binding of its cell attachment site induces
a state of B cell tolerance, permitting infection to proceed unchecked.
Our covalent vaccination approach breaks the tolerance and stimulates
production of antibodies that inactivate the virus."
The tolerance signal is converted to a stimulatory signal because
strong covalent binding to the B cells liberates a large amount of
energy that is not available in traditional binding reactions, Paul
said. Moreover, the prototype vaccine contains two modular antigenic
regions. Binding of one region generates a stimulatory signal that
overcomes the tolerance signal.
"There is another advantage. B cells have the unique capability of
producing antibodies adapted to recognize the chemical groups we placed
in the prototype vaccine. The adaptations impart enzyme-like activity to
the antibodies, which results in exceptionally stable HIV binding, and
sometimes, in catalytic breakdown of the viral coat. Consequently, the
antibodies inactivate HIV effectively," Paul said.
"The failure of previous HIV vaccine trials has produced pessimism
about the prospect of effective HIV vaccination. Our approach is
promising but additional studies are necessary. To expedite development
of the vaccine, we must maximize the antibody response and focus it even
more at the HIV cellular attachment site," said Yasuhiro Nishiyama, PhD,
lead author and an associate professor at UT Medical School.
"While the prototype vaccine induces antibodies that neutralize
infection of isolated human cells, we must also show that the antibodies
prevent the natural process of infection within the body," said
Stephanie Planque, PhD, co-author and researcher in Paul's laboratory.
"The induction of antibodies that neutralize infection of human blood
cells by diverse strains of HIV from various parts of the world is an
important milestone. This is an entirely new vaccination approach that
might bypass the natural constraints on developing effective immunity
against HIV," said Carl Hanson, Ph.D., study co-author and head of the
Retrovirus Diagnostic Section of the Viral and Rickettsial Disease
Laboratory of the California Department of Public Health.
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