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Engineering antibodies against HIV

04 Feb, 2014

A team of medical researchers from the Rockefeller University, New York, and the Harvard Medical School, Boston, is on the brink of developing a new effective HIV vaccine and treatment.

This will replace therapeutic antibodies against which HIV has developed resistance.

Effective against number of HIV-1 strains

Led by long-time AIDS researcher Professor David Ho, the team has developed a method of engineering an antibody called ibalizumab, which appears effective against a large number of HIV-1 strains. They suggest the same approach might also be useful to resurrect the therapeutic potency of other antibodies.

Unmodified ibalizumab is already in clinical studies in HIV-infected individuals, showing a good safety profile and a well documented antiviral effect, and is also being studied as a preventative in uninfected subjects.

Acts by binding to a receptor

The existing unmodified ibalizumab antibody acts by binding to a receptor called CD4, which HIV-1 uses to enter cells. This binding action blocks HIV-1 infection. However, HIV-1 strains in some patients treated with ibalizumab acquire particular mutations that make them resistant to the antibody. Structural studies have showed that these mutations loosen the interaction between HIV-1 and ibalizumab by introducing a gap between the virus and the antibody.

Suspecting that this gap contributes to HIV-1 resistance, Professor Ho and colleagues reasoned that ‘refilling’ it would counter the virus’s evasive manoeuvre. To test this theory, they engineered a number of tagged ibalizumab antibodies with a carbohydrate called glycan, inserted near the site of interaction with the virus. One of the carbohydrate-tagged antibodies (with the glycan at a specific location) neutralised 100% of the 118 diverse HIV-1 strains tested in vitro, including 10 strains resistant to the unmodified antibody. This very promising result demonstrates that the strategic placement of a glycan in the variable region of a monoclonal antibody can substantially boost its antiviral potency.

Stopping the spread of AIDS in China

Professor Ho, a senior physician and head of department at the Rockefeller University, has been studying AIDS and HIV for over 30 years and has published some 375 papers in the area. He is involved in stopping the spread of AIDS in China, with his team establishing a number of public education and medical initiatives to address the problem. His team was the first to administer effective antiretroviral therapy in China, and they are leading the way in implementing best practices to block mother-to-child transmission of HIV in the Yunnan Province.

The research was published in the November 2013 issue of Nature Biotechnology.


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