October 27, 2008

Novel Type of Antibody Inhibits HIV Infection

Illustration of HIV viruses

Researchers have identified a small antibody fragment that is highly effective at neutralizing the human immunodeficiency virus (HIV). The finding may lead to new treatments against HIV and other viruses.

Treating people with HIV is difficult because the virus is able to mutate and become resistant to antiretroviral drugs. More than half of patients in the United States receiving antiretroviral therapy for their HIV infection are thought to carry virus strains that are resistant to at least one of the currently available antiretroviral drugs.

It's difficult to develop a vaccine against HIV for the same reason. Most vaccines work by triggering the immune system to produce antibodies that help to beat back infections. But the proteins on the surface of HIV mutate rapidly and change shape continuously, preventing most antibodies from latching onto and neutralizing the virus.

NIH scientists have focused recently on an HIV surface protein known as gp120, or Env. HIV needs this protein to grip and gain entry to the T cells it infects. The researchers identified an unchanging region of Env as a potential site of viral weakness. However, antibodies are large proteins and can't easily access this unchanging region.

Antibodies all have the same overall structure, but vary in a small region at the tip. That's how millions of different antibodies can bind to different targets, known as antigens. Previous research has shown that antibodies can be reduced to small, independently functional fragments. 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, however, they're able to access targets that can't be reached by whole antibodies.

In an earlier study, a team of researchers led by Dr. Dimiter S. Dimitrov of NIH's National Cancer Institute (NCI) screened a large library of antibodies and identified a unique antibody called m0 that could bind the HIV protein Env. In the current study, they constructed a library of 25 billion different dAbs based on m0's framework. They then screened the dAbs against Env proteins from 2 different strains of HIV.

The researchers reported in the October 21, 2008, edition of Proceedings of the National Academy of Sciences that they identified a dAb, m36, that binds strongly to different Env proteins and blocks a broad range of HIV strains from entering their target cells. The scientists believe that m36 represents the first human dAb against HIV.

“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 team is now working to test combinations of m36 and other HIV inhibitors. They're also attempting to construct more potent versions of m36. In addition, the team is using this approach to identify dAbs against cancer and other disease-related antigens.

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