HIV surface protein's weak point detected; new lead for antibody-based vaccine?

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US scientists say they may have found the site on HIV’s outer coating that would be most vulnerable to antibodies that could neutralise the virus and prevent it from infecting human cells. Their work, using crystallisation and atomic-level photography, is published this week in the journal Nature.

Previous efforts to develop vaccines that could stimulate the production of antibodies capable of binding to the proteins on HIV’s envelope – thus preventing HIV from engaging with its target cells in the human body – have all foundered because the HIV envelope proteins vary too much from one virus to another.

The variation in envelope proteins is driven by the immune system, which forces the virus to constantly change the pattern of amino acids on its surface. Further difficulty is posed by the flexibility of the chemical bonds in the gp120 proteins which form spikes on the surface of the virus.

Glossary

gp120

A glycoprotein on the HIV envelope. gp120 binds to a CD4 receptor on a host cell, such as a CD4 T lymphocyte (CD4 cell). This starts the process by which HIV fuses its viral membrane with the host cell membrane and enters the host cell.

receptor

In cell biology, a structure on the surface of a cell (or inside a cell) that selectively receives and binds to a specific substance. There are many receptors. CD4 T cells are called that way because they have a protein called CD4 on their surface. Before entering (infecting) a CD4 T cell (that will become a “host” cell), HIV binds to the CD4 receptor and its coreceptor. 

CD4 receptor

A molecule on the surface of some cells onto which HIV can bind. To enter a host cell, HIV binds to a CD4 receptor and a coreceptor (either CCR5 or CXCR4) on the host cell. CD4 receptors are found on CD4 cells, other types of T cells, macrophages, monocytes, and dendritic cells.

epitope

The part of an antigen which the immune system recognises. 

envelope

The outer surface of a virus, also called the coat. Not all viruses have an envelope. In the case of HIV, the envelope contains two viral proteins (gp120 and gp41), which are initially produced as a single, larger protein (gp160) that is then cleaved in two. 

These spikes engage with the CD4 receptor on the surface of lymphocytes and other cells in order to begin the process of HIV entry into the cell.

Researchers have been looking for a way of blocking this interaction by inducing antibodies that can lock onto gp120 and prevent engagement with the CD4 receptor, but experiments have persistently failed.

Part of the reason for this failure is the ability of HIV’s gp120 to change its shape as a result of coming into contact with the CD4 receptor, a process known as conformational masking.

In order to track how gp120 changes shape during its engagement with the CD4 receptor, and when it might be most vulnerable to antibody interference, Peter Kwong and colleagues at the US National Institute of Allergy and Infectious Disease (NIAID) Vaccine Research Center created variants of gp120 that had been fixed in the shapes they take as they initiate binding to the CD4 receptor.

Then they photographed the molecular structure of the antibody that fitted the binding site most closely. The team had to use crystallisation of the proteins in order to capture the forms.

The site they identified is tucked away and impossible for antibodies to reach until the interaction with the CD4 receptor begins. Antibodies to this site, known as b12 antibodies, are more likely to be found in HIV-positive people who are long-term non-progressors, according to research presented at the AIDS Vaccine `06 meeting in Amsterdam.

They saw that b12 binds gp120 at the same point where gp120 initially attaches to CD4. Unlike the gp120-CD4 interactions, however, b12 can latch onto the site of CD4's first contact without requiring a shape change in gp120 to create a stable bond between the two molecules. Essentially, the scientists found that the initial point of CD4 contact is a site of gp120 weakness because it is the site of recognition - called an epitope - for b12.

"One of our primary goals is to develop HIV vaccines that can stimulate broadly neutralising antibodies," said Dr Gary Nabel, director of the NIAID Vaccine Research Center.

"The structure of this gp120 epitope, and its susceptibility to attack by a broadly neutralising antibody, shows us a critical area of vulnerability on the virus that we may be able to target with vaccines. This is certainly one of the best leads to come along in recent years."

Vaccine developers will now have to construct vaccine candidates that contain the gp120 epitope, and test them in small preliminary studies. Progress towards larger studies of antibody-based HIV vaccines will require proof that the vaccine produces consistent antibody responses in humans.

References

Zhou T et al. Structural definition of a conserved neutralization epitope on HIV-1 gp120. Nature 445: 732-737, 2007.