|Researchers Identify Novel Type of Antibody that Potently Inhibits HIV Infection
A small antibody fragment that is highly effective in neutralizing the human
immunodeficiency virus (HIV) by preventing the virus from entering
cells has been identified by researchers at the National Cancer
Institute (NCI), part of the National Institutes of Health (NIH).
This finding may provide insight into the development of new treatments
against HIV and other viruses, hopefully in the not too distant
future. The study appears online Oct. 20, 2008, in Proceedings
of the National Academy of Sciences.
Treating HIV-infected individuals is difficult because the virus is able to mutate
and become resistant to antiretroviral drugs. "In the United States,
it is estimated that more than 50 percent of patients who are receiving
antiretroviral therapy for their HIV infection carry strains of
the virus that are resistant to treatment with at least one of
the currently available antiretroviral drugs," said NCI Director
John E. Niederhuber, M.D. "The development of new drugs against
HIV is an urgent public health need."
Antibodies are large proteins naturally produced by the immune system to help
fight disease-causing foreign invaders, such as viruses and bacteria. Although
the general structure of all antibodies is very similar, a small region at the
tip of the protein is extremely variable, allowing millions of antibodies, characterized
by slightly different tip structures, to exist and bind to different targets,
known as antigens. Previous research has shown that reducing antibodies to the
smallest independently functional fragment, known as a variable domain, can extend
their utility as therapeutic agents. These fragments, called domain antibodies
(dAbs), retain the variable tip structure and, therefore, the antigen-binding
specificity of the parent antibody. Because of their small size, they are able
to access targets that cannot be reached by much larger, whole antibodies.
In an earlier study, the researchers identified a unique antibody, called m0,
while screening a large library of antibodies directed against the HIV protein,
Env (also known as gp120). The library contained the variable portions of antibodies
that can bind to Env antigens. "We found an antibody fragment that exhibited
the ability to neutralize HIV and had properties that allowed us to construct
a novel library containing dAbs directed against HIV," said Dimiter S. Dimitrov,
Ph.D., of NCIís Center for Cancer Research.
Based on m0ís framework, the leading author of the study, Weizao Chen, Ph.D.,
constructed a very large library of dAbs (25 billion different dAbs), screened
it against Env proteins from two different strains of HIV, and identified a dAb,
m36, that bound strongly to different Env proteins and blocked the infectivity
of a broad range of HIV strains. The researchers believe that m36 represents
the first human dAb against HIV reported.
"The antibody fragment that we identified, m36, could have potential in the development
of a therapeutic drug that inhibits HIV," said Dimitrov. "Further research with
this molecule also could offer insight about how the virus infects cells and
how it evades neutralization by the immune system."
The research team is working to test various combinations of m36 with other inhibitors
that may be effective against HIV. The team is also attempting to construct more
potent versions of m36. Partnership with industry could speed the ability to
evaluate m36 as a potential treatment for HIV. Dimitrovís team is also using
this approach to identify dAbs against cancer and other disease-related antigens.
For more information on Dr. Dimitrovís research, please go to http://ccr.cancer.gov/staff/staff.asp?profileid=5749.
NCI leads the National Cancer Program and the NIH effort to dramatically reduce
the burden of cancer and improve the lives of cancer patients and their families,
through research into prevention and cancer biology, the development of new interventions,
and the training and mentoring of new researchers. For more information about
cancer, please visit the NCI Web site at http://www.cancer.gov or call NCI's
Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).
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Medical Research Agency — includes 27 Institutes and
Centers and is a component of the U.S. Department of Health and
Human Services. It is the primary federal agency for conducting
and supporting basic, clinical and translational medical research,
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Reference: Chen, W, Zhu Z, Feng Y, Dimitrov DS. Human domain antibodies to conserved
sterically restricted regions on gp120 as exceptionally potent cross-reactive
HIV-1 neutralizers. Proceedings of the National Academy of Sciences. Online October