Two human antibodies that can stop over 90% of known HIV strains from infecting human cells in the lab have been discovered by scientists. They have also demonstrated how one of these proteins manages to stop HIV strains.

The researchers say that these antibodies could be used to create better HIV vaccines, and may be further developed to prevent or treat HIV infection. The method used to find these antibodies could also be applied to isolate therapeutic antibodies for other infectious diseases.

Anthony S. Fauci, M.D., Director, the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, said:

“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.

In addition, the technique the teams used to find the new antibodies represents a novel strategy that could be applied to vaccine design for many other infectious diseases.”

The researchers, led by a team from the NIAID Vaccine Research Center (VRC), found two naturally occurring, powerful antibodies called VRC01 and VRC02 in an HIV infected person’s blood using a novel molecular device they developed that targets the precise cells that create HIV antibodies. The device is an HIV protein that the researchers adapted so it would react only with antibodies specific to the site where the virus binds to cells it infects.

The researchers discovered that VRC01 and VRC02 neutralize more HIV strains with greater overall strength than other previously known virus antibodies.

The scientists also determined the atomic-level structure of VRC01 when it attaches to HIV, allowing them to define how the antibody works and to precisely pinpoint where exactly it attaches to the virus. With this knowledge, they have started to design components of a candidate vaccine that could teach the human immune system to manufacture antibodies comparable to VRC01 that could prevent infection by the most HIV strains present in the world today.

NIAID scientists Peter D. Kwong, Ph.D., John R. Mascola, M.D., and Gary J. Nabel, M.D., Ph.D., led the two research teams. A pair of articles about these findings appears today in the online edition of Science.

Dr. Nabel, the VRC director, explained:

“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.”

As the virus continuously changes its surface proteins to evade recognition by the immune system, finding individual antibodies that can neutralize HIV strains anywhere has been extremely challenging. As a result of these changes, a huge number of HIV variants exist worldwide. Even so, scientists have identified a few areas on HIV’s surface that remain nearly constant across all variants. One such area, located on the surface spikes used by HIV to attach to immune system cells and infect them, is called the CD4 binding site. VRC01 and VRC02 block HIV infection by attaching to the CD4 binding site, preventing the virus from latching onto immune cells.

Dr. Mascola, the deputy director of the VRC, said:

“The antibodies attach to a virtually unchanging part of the virus, and this explains why they can neutralize such an extraordinary range of HIV strains.”

With these antibodies in hand, a team led by Dr. Kwong, chief of the structural biology section at the VRC, determined the atomic-level molecular structure of VRC01 when attached to the CD4 binding site. They then examined this structure in light of natural antibody development to ascertain the steps that would be needed to elicit a VRC01-like antibody through vaccination.

Antibody development starts with the mixing of genes into new combinations within the immune cells that make antibodies. Examination of the structure of VRC01 attached to HIV suggested that, from a genetic standpoint, the immune system likely could produce VRC01 precursors readily. The researchers also confirmed that VRC01 does not bind to human cells – a characteristic that might otherwise lead to its elimination during immune development, a natural mechanism the body employs to prevent autoimmune disease.

In the final stage of antibody development, antibody-producing B cells recognize specific parts of a pathogen and then mutate, or mature, so the antibody can bind to the pathogen more firmly. VRC01 precursors do not bind tightly to HIV, but rather mature extensively into more powerfully neutralizing forms. This extensive antibody maturation presents a challenge for vaccine design. In their paper, Dr. Kwong and colleagues explore how this challenge might be addressed by designing vaccine components that could guide the immune system through this stepwise maturation process and facilitate the generation of a VRC01-like antibody from its precursors. The scientists currently are performing research to identify these components.

Dr. Kwong said:

“The discoveries we have made may overcome the limitations that have long stymied antibody-based HIV vaccine design.”

The two research teams included NIAID scientists from the VRC, the Laboratory of Immunoregulation, and the Division of Clinical Research, all in Bethesda, Md.; as well as researchers from Beth Israel Deaconess Medical Center in Boston; Columbia University in New York; Harvard Medical School and Harvard School of Public Health in Boston; The Rockefeller University in New York City; and University of Washington in Seattle.

“Structural Basis for Broad and Potent Neutralization of HIV-1 by Antibody VRC01”
Tongqing Zhou, Ivelin Georgiev, Xueling Wu, Zhi-Yong Yang,1, Kaifan Dai, Andrés Finzi, Young Do Kwon, Johannes Scheid, Wei Shi, Ling Xu, Yongping Yang, Jiang Zhu,1 Michel C. Nussenzweig, Joseph Sodroski, Lawrence Shapiro, Gary J. Nabel, John R. Mascola,1 Peter D. Kwong
Published Online July 8, 2010
Science DOI: 10.1126/science.1192819

Written by Christian Nordqvist