July 16, 2010
2 min read
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Pair of monoclonal antibodies may lead to development of HIV vaccine

Wu X. Science. 2010; doi:10.1126.science.1187659.

Zhou T. Science. 2010; doi:10.1126/science.1192819.

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Two human antibodies discovered in the blood of a patient with HIV-1 have the potential to prevent infection from more than 90% of circulating HIV strains, according to data from two studies.

In the first study, researchers from the National Institute of Allergy and Infectious Diseases’ Vaccine Research Center (VRC) developed a resurfaced version of the HIV-1 envelope protein that was designed to react only with antibodies specific to the CD4-binding site — the region at which cell infection occurs and one of the few constants present in the numerous, highly mutable HIVstrains.

Of the multiple scientifically modified proteins, the researchers selected the resurfaced stabilized core 3, also referred to as RSC3, for further studies due to its strong reactivity to CD4-binding site antibodies and little or no reactivity to those attacking other parts of the protein.

“We have used our knowledge of the structure of a virus — in this case, the outer surface of HIV — to refine molecular tools that pinpoint the vulnerable spot on the virus and guide us to antibodies that attach to this spot, blocking the virus from infecting cells,” study researcher and VRC director Gary J. Nabel, MD, said in a press release.

Two somatic variants of monoclonal antibodies — VRC01 and VRC02 — exhibited the greatest ability to neutralize HIV-1 isolates by binding strongly to the glycoprotein 120 (gp120) in a manner similar to the interaction between CD4 and gp120. “This observation may explain their impressive breadth and reactivity,” the researchers wrote. “The isolation of these [monoclonal antibodies] from an HIV-1 infected subject and the demonstration that they neutralize the vast majority of HIV-1 strains by targeting the functionally conserved receptor binding region of [HIV-1 envelope] provides proof of concept that such antibodies can be elicited in humans.”

The second study examined the basis of VRC01 neutralization more closely to understand how the antibody may play a role in vaccine creation. The researchers found that the VRC01 interaction with gp120 covers 98% of the outer domain-contact site for CD4, and this extensive coverage provides the antibody with greater capacity for recognition.

“Accumulating evidence suggests that VRC01 defined mode of recognition is used by other antibodies,” the researchers wrote. “These findings suggest that VRC01 is not an isolated example and likely provides a template for a general mode of recognition. The structure-function insights of VRC01 described here, thus, provide a foundation for rational vaccine design based not only on the particular mode of antibody-antigen interaction but also on defined relationships between genomic antibody precursors, somatic hypermutation and required recognition elements.”

“The discovery of these exceptionally broadly neutralizing antibodies to HIV and the structural analysis that explains how they work are exciting advances that will accelerate our efforts to find a preventive HIV vaccine for global use,” said Anthony S. Fauci, MD, director of NIAID. He also added that the technique used to discover these antibodies may hopefully be generalized and used for creating vaccines for other infectious diseases.