Scientists have uncovered new information that may help guide design of vaccines for HIV-1, the virus that causes AIDS. A new detailed structural analysis of the complex formed by an anti-HIV antibody called 4E10 and its specific target provides insight into why this particular antibody is so broadly effective, a rare characteristic for HIV discovered thus far. The research is published in the February issue of Immunity.
Vaccination has been a successful strategy for protecting humans from many potentially harmful viruses. However, designing a suitable vaccine for HIV-1 has been a highly challenging and thus far unsuccessful endeavor. HIV-1 is enormously variable and it has been difficult to isolate antibodies that will recognize the many different strains of the virus. The antibody 4E10 was derived from HIV-1 infected patients by Dr. Hermann Katinger in Vienna and is the broadest acting neutralizing antibody against HIV-1 that is currently known. This antibody recognizes a protein called gp41 that is found on the surface of the virus. The gp41 protein is thought to play a key role in mediating entry of HIV-1 into human cells.
A research group led by Drs. Dennis R. Burton and Ian A. Wilson from The Scripps Research Institute in La Jolla, California performed a study examining the detailed molecular structure of the complex formed when 4E10 binds to gp41 and determining how interaction of 4E10 with gp41 influences the virus.
X-ray crystallography was used to determine the structure of the complex formed by association of 4E10 with a peptide fragment that is identical to the section of gp41 that the antibody recognizes. The researchers identified the specific amino acids on gp41 that 4E10 interacts with and the 3D structure adopted by these amino acids. These study results suggest that 4E10 interacts with gp41 at a conserved region very close to the surface of the virus and they reveal some special characteristics of 4E10 that make it unusually effective at targeting this region.
Drs. Burton and Wilson are members of a scientific consortium of laboratories, the International AIDS Vaccine Initiative’s Neutralizing Antibody Consortium (IAVI), which is focused on understanding broadly neutralizing antibodies at the molecular level and transferring this knowledge into the design of vaccines capable of stimulating broadly neutralizing antibodies against globally diverse HIV. According to Dr. Wayne Koff, IAVI Sr. VP for Vaccine Research, “Elucidation of the critical features of 4E10 recognition of HIV-1 helps to define potential immunogens able to elicit 4E10-like antibodies. This is an excellent example of the tremendous potential for accelerating HIV vaccine design when scientists from multidisciplinary laboratories come together to tackle a major scientific challenge. ”
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Rosa M.F. Cardoso, Michael B. Zwick, Robyn L. Stanfield, Renate Kunert, James M. Binley, Hermann Katinger, Dennis R. Burton, and Ian A. Wilson: “Broadly Neutralizing Anti-HIV Antibody 4E10 Recognizes a Helical Conformation of a Highly Conserved Fusion-Associated Motif in gp41”
Publishing in Immunity, Volume 22, Number 2, February 2005, pages 163&endash;173. http://www.immunity.com/
