Tongqing Zhou on a New Antibody to Neutralize HIV-1

Fast Breaking Papers Commentary, August 2011

Tongqing Zhou

Article: Structural Basis for Broad and Potent Neutralization of HIV-1 by Antibody VRC01


Authors: Zhou, TQ;Georgiev, I;Wu, XL;Yang, ZY;Dai, KF;Finzi, A;Kwon, YD;Scheid, JF;Shi, W;Xu, L;Yang, YP;Zhu, JA;Nussenzweig, MC;Sodroski, J;Shapiro, L;Nabel, GJ;Mascola, JR;Kwong, PD
Journal: SCIENCE
Volume: 329, Issue: 5993, Page: 811-817, Year: AUG 13 2010
* NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA.
* NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA.
(Addresses have been truncated)

Tongqing Zhou talks with ScienceWatch.com and answers a few questions about this month's Fast Breaking Paper paper in the field of Microbiology.


SW: Why do you think your paper is highly cited? Does it describe a new discovery, methodology, or synthesis of knowledge?

My paper describes how a new antibody, VRC01, neutralizes >90% of HIV-1 strains. It visualizes the structural basis for broad and potent neutralization by this naturally elicited human antibody, which attacks the HIV virus by partially mimicking the natural receptor for HIV-1.

Discovery of broad and potent HIV-1 antibodies from natural infection has been and still is a hot field in HIV research. In a companion paper, my colleague and I describe the discovery of antibody VRC01 using a molecular probe specially designed to fish out antibodies that target the primary receptor binding site on HIV-1's envelope.

COOKIES
This image shows the atomic level protein structure of the antibody VRC01 (blue and green) binding to HIV (grey and red). The precise site of VRC01-HIV binding (red) is a subset of the area of viral attachment to the primary immune cells HIV infects.

IMAGE Credit: NIAID VRC
.

The application of structurally designed probes in antibody discovery is a novel concept that can be applied to identify new antibodies to HIV or other infectious agents. Definition of the epitope and elucidation of the neutralization mechanism of antibody VRC01 will facilitate the rational design of an effective vaccine.

SW: Would you summarize the significance of your paper in layman's terms?

Previously, it was thought that antibodies could not effectively stop HIV from infecting human cells because of the virus's enormous diversity. We show a single human antibody is up to the task!

The discovery of antibody VRC01, together with the structural definition of its neutralization mechanisms, showed for the first time that it's possible for a human to make an antibody that can powerfully and effectively neutralize the vast majority of known HIV strains in the laboratory. Our research advance has boosted optimism about creating an HIV vaccine that induces this kind of antibody and is a milestone in the race for an HIV vaccine.

SW: How did you become involved in this research, and how would you describe the particular challenges, setbacks, and successes that you've encountered along the way?

I joined the Vaccine Research Center (VRC) at NIAID, NIH, on September 11, 2001, a date I will never forget. This year marks the 10th year I am in HIV research. I cannot believe that I have taken part in one-third of the history of HIV studies.

My research is mainly focused on the structural basis of HIV immune evasion as well as the mechanisms of broadly neutralizing antibodies. In the early years, while designing and studying HIV gp120 proteins in different conformational states, we were puzzled by the phenomena that their association rates to the receptor CD4 on human immune cells—the molecule that HIV first attaches on the cells it infects—did not vary.

After many repeated experiments and discussions with colleagues, we realized that the viral site for initial CD4 attachment actually does not change conformation. Together with the crystal structure of antibody b12, a phage display-identified HIV neutralizing antibody that targeted the CD4 binding site, this finding led to the identification of a site of vulnerability at the primary receptor CD4 binding site on the HIV-1 viral envelope. The publication of our findings in Nature in 2007 brought global media attention.

To better define the site of vulnerability, my colleagues and I also studied the structural details of two representative non-neutralizing antibodies that targeted the CD4 binding site. The results, published in Science in 2009, indicated that these antibodies induced conformational changes on the HIV envelope protein that were not allowed on the viral spike.

"In the future, the elucidation of VRC01's neutralization mechanism and the pathway for eliciting it may provide a roadmap to the development of an effective HIV-1 vaccine. Imagine a world without AIDS!"

The next step was to design immunogens that incorporated the knowledge we gained about the site of vulnerability. However, animal tests with our designed immunogens did not yield desired antibodies. We were all somewhat disappointed. Things took a turn when Dr. Gary Nabel, director of the VRC, once pointed out in a joint lab meeting that these immunogens might be useful for interrogating patient sera to identify natural human antibodies that targeted the site of vulnerability. A campaign of antibody discovery jointly by different VRC labs began and that led to the successful discovery and characterization of VRC01.

Through these years of research, I strongly feel that the momentum of breakthrough is always brought by accumulation of knowledge. Big science, such as HIV-1 vaccine development, requires a collection of expertise from different areas and cannot be accomplished by a single lab. The story of VRC01 discovery is a good example of how close collaboration produced breakthrough results. The VRC is organized in a way to promote collaboration and enable scientists to achieve.

SW: Where do you see your research leading in the future?

Our ultimate goal is, of course, an effective HIV-1 vaccine. Before a vaccine based on this work can stimulate the human body to produce antibodies like VRC01, there are several critical steps to go. First, we need to determine if this kind of antibody can be generated in the vast majority of the population rather than in a selected few; VRC01 was discovered from an HIV-1 infected non-progressor with extensive affinity maturation mutations. In this published paper we showed that the non-matured antibody did not neutralize most HIV strains.

It is critical to understand how affinity maturation leads to the breadth and potency of antibody VRC01. The clinical application of VRC01 is another exciting prospect on the horizon.

SW: Do you foresee any social or political implications for your research?

When traditional vaccine strategies fail, we turn to natural antibodies for clues. The discovery of VRC01 proved that the human immune system can actually produce a broad and potent neutralizing antibody to HIV, and this brought new optimism to HIV-1 vaccine research. In the future, the elucidation of VRC01's neutralization mechanism and the pathway for eliciting it may provide a roadmap to the development of an effective HIV-1 vaccine. Imagine a world without AIDS!End

Tongqing Zhou, Ph.D.
Staff Scientist
Structural Biology Section
Vaccine Research Center
National Institute of Allergy and Infectious Diseases
National Institutes of Health
Bethesda, MD, USA

KEYWORDS: HIV-1, ANTIBODY VRC01, GP120 ENVELOPE GLYCOPROTEIN, RECEPTOR, SITE, EPITOPE, SURFACE, INDIVIDUALS, ATTACHMENT, MATURATION, HYPOTHESIS, VACCINES.

 
 

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