Is an HIV vaccine finally possible? Unraveling the secrets of broadly neutralizing antibodies

Last month I talked about the daunting challenge that HIV has presented for the past thirty years. HIV is so variable that as soon as the immune system builds a defense against it, the virus comes up with a new variant that allows it to escape. The only way to defeat such an elusive enemy is with immune responses able to recognize a broad range of HIV subtypes and variants. Unfortunately, antibodies with these characteristics are produced by a minority of patients and only years into the infection, failing to prevent progression to AIDS, the disease caused by HIV. The few vaccine trials conducted in the past decade have failed to elicit proper immune responses. 

The surface (envelope) of the virus looks like this:

Those "mushroom-like"structures (a complex of two proteins) on the envelope are the "handles" the virus uses to dock with the target cells. Once the virus has linked the target cell, it injects its RNA inside, and the infection begins. One way antibodies neutralize the virus, is by "capturing" those handles on its surface and thus preventing it to dock with the cells. Imagine putting a plug into a socket--nothing else can go into that socket anymore. The problem is that these "handles" are very well shielded underneath a coat of sugar molecules, which makes them "slippery" (to use another analogy). Furthermore, the virus changes constantly around them, and this variability allows it to dodge the several attempts the antibodies make to grab it. 

But there's hope at the end of the tunnel.

Two studies published in the latest issue of Science [1, 2] present a new class of broadly neutralizing antibodies and describe the mechanism by which they block the virus, thus giving new insight on how to "teach" the immune system to develop this kind of defenses.

The new class of antibodies found in [1, 2] have been isolated from chronically infected patients, and some of them, like VRC01, are able to neutralize a shocking 90% of different HIV isolates. (When I started working on HIV, five years ago, the best neutralizing antibodies would recognize a mere 40% of the isolates.) The amazing bit is that they do so by mocking the very same mechanism the virus uses to dock with target cells.

It took years for these patients to produce these specials antibodies. These findings show that, though slowly, the immune system can develop appropriate responses to defeat the virus. This process is currently too slow to protect from the infection (the antibodies are produced too late), however, by understanding how these antibodies bind to the virus (which is done using deep sequencing and x-ray crystallography), researchers can learn how they have evolved and, eventually, how to elicit them through a vaccine.

REFERENCES:
[1] Wu, X., Zhou, T., Zhu, J., Zhang, B., Georgiev, I., Wang, C., et al. (2011). Focused Evolution of HIV-1 Neutralizing Antibodies Revealed by Structures and Deep Sequencing Science, 333 (6049), 1593-1602 DOI: 10.1126/science.1207532
[2] Scheid, J., Mouquet, H., Ueberheide, B., Diskin, R., Klein, F., Oliveira, T., et al. (2011). Sequence and Structural Convergence of Broad and Potent HIV Antibodies That Mimic CD4 Binding Science, 333 (6049), 1633-1637 DOI: 10.1126/science.1207227

Photo: wind sculpture, Santa Fe, NM. Canon 40D, focal length 85mm, ISO 100, shutter speed 1/100, F-stop 8.0.