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Artificial HIV Gene Could Aid Vaccine Development

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Duke Health News 919-660-1306

DURHAM, N.C. – Duke University Medical Center researchers have shown
that the protein produced by an artificial HIV-1 gene triggers
anti-HIV-1 immune responses in animals. Such proteins -- produced by
genes engineered to have "centralized" structures similar to those in
several HIV strains -- could serve as a basis for vaccines that protect
against many strains. Showing that artificial genes produce
biologically functional proteins is a significant step in HIV vaccine
development, the researchers said.

"This study is proof we can
induce both cellular and humoral immune responses using an artificial
HIV-1 gene. This is a beachhead from which we can move forward in
vaccine development," said Feng Gao, M.D., associate research professor
of medicine at Duke University Medical Center and lead author of the
study. Cellular immune responses are those made by specialized immune
cells, called killer T cells and helper T cells; while humoral immune
responses are those made by proteins called antibodies circulating in
the blood.

The researchers published their findings in the
January 2005 issue of the Journal of Virology. The study was funded by
the National Institute of Allergy and Infectious Diseases, National
Institutes of Health.

In their experiments, Gao and his
colleagues found the protein produced by the artificially synthesized
HIV-1 envelope gene, called CON6, works similarly to corresponding
natural HIV-1 proteins. The protein binds to surface molecules on the
human immune system cells that are the primary portal by which HIV-1
enters and infects the cells. Also, they found, antibodies in blood
from humans infected with different HIV-1 subtypes recognized and
reacted with the protein from the CON6 gene better than "wild type" HIV
envelope proteins.

In guinea pigs, the protein successfully
induced neutralizing antibodies against some HIV-1 strains, although
the level was weak. And in mice, vaccines made with the artificial gene
induced an anti-HIV-1 response in T cells, the immune system's
principal infection fighters.

The synthetic CON6 gene was
designed via computer at Los Alamos National Laboratory to be
"centralized" -- as similar as possible to many genetic subtypes of the
most common strains of HIV-1 in the world. The strains, known as M
group, contain nine subtypes and are responsible for over 90 percent of
global infections. The researchers hope the new gene will help
circumvent HIV-1's high levels of genetic variation, which may give the
virus an ability to evade attack by an immune system primed to
different genetic variants.

"The variations among HIV-1 subtypes
make vaccine development very difficult," Gao said. "Centralized genes,
designed on computers, could be useful in developing vaccines for areas
where several HIV-1 subtypes are circulating. However, because
centralized genes are artificially made, there has been great concern
that these genes might not be able to perform the biological functions
of native genes," he said.

The human body produces an immune
response against HIV-1 about two to four weeks after exposure to the
virus. Killer T cells and B cells reduce HIV-1 levels by attacking the
invading virus and infected cells. Despite this massive effort, some
HIV-1 can escape the body's defenses, especially if the virus mutates
within its human host and is no longer vulnerable to the original
immune responses. A vaccine that stimulates both cross-reactive
neutralizing antibody and T cell responses against HIV-1 could be the
best way to protect against infection, said Gao. Cross-reactive
neutralizing antibodies are those that can attack multiple HIV strains.

The
protein produced by CON6 differs by only about 15 percent in its
sequences of amino acids from the corresponding natural genes in the
nine HIV-1 subtypes in group M. This difference represents only about
half the natural difference among the subtypes. Amino acids are the
building block molecules of proteins. The CON6 gene was generated by
choosing common amino acid sequences from the HIV-1 subtypes.

Study
co-authors include Eric A. Weaver and Zhongjing Lu of Duke; Yingying Li
of the University of Alabama at Birmingham; Hua-Xin Liao, Benjiang Ma,
S. Munir Alam, Richard M Scearce, Laura L. Sutherland and Jae-Sung Yu
of Duke; Julie M. Decker and George M. Shaw of the Howard Hughes
Medical Institute in Birmingham, Ala.; David C. Montefiori of Duke;
Bette T. Korber of Los Alamos National Laboratory; Beatrice H. Hahn of
the University of Alabama at Birmingham; and Barton F. Haynes of Duke.

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