Saturday, September 17, 2011

A promising new lead for HIV vaccination

Antibodies that bind to an HIV molecule responsible for entry of the virus into the cell, could possibly be used in a vaccine that protects against HIV infection. Studies have shown that so called broadly neutralizing antibodies (BNAbs) are able to bind to the virus in such a manner that entry into T-lymphocytes, immune cells that are normally infected by HIV, is inhibited. A specific version of these BNAbs, called VRC01 is the most promising when it comes to blocking infection.

The mechanism by which HIV infects a T-lymphocyte relies on contact of the viral envelope (ENV) with the CD4 receptor of the lymphocyte. When the two connect, a co-receptor is revealed by a structural change in the virus. Consequently, a cascade is triggered that eventually leads to entry of HIV into the cell. Because connecting ENV with CD4 is of paramount importance in the infection process, blocking ENV with antibodies is a promising therapeutic target. So far, however, no suitable candidates have been developed.

VRC01, which serves as a prototype antibody, could be different. It binds specifically to the part of the ENV that is used to connect it with the CD4 receptor on the T-cell. When the antibody binds to ENV, it is unable to perform its task of binding to CD4. This may stop the whole infection cascade, rendering HIV unable to infect cells, which in turn prevents the development of AIDS. Studies with VRC01 show that it is able to neutralize 90 percent of the tested HIV isolates, a remarkable high efficacy.

BNAbs are not only something scientists create in the lab: they are also produced by the immune system in response to HIV infection. However, mostly the antibody response is not potent enough, and arrives too late after infection. It is known that humans possess a fair amount of antibody variants with VRC01-like properties. This could also serve as an explanation for the fact that some patients are resistant against HIV infection, and do not develop AIDS.

After studying the characteristics of these VRC01-like antibodies, it appears that the variants that are highly effective in inhibiting HIV infection share a strong affinity for binding to a specific part of ENV. The gp120 protein, that is part of the viral envelope of HIV is the most predominant target of the VRC01 antibodies. When analyzing the antibody sequence, scientists found that a gp120 affinity was the most conserved part of the VRC01 antibodies in humans. It was already known that gp120 is essential for viral entry into the cell, highlighting the way by which VRC01 inhibits viral infection.

Structural analysis of viral binding sites and their corresponding compatible antibodies showed that developing an effective HIV vaccin might not be that far away. Of course, between showing binding affinity and injecting an actual vaccine into a patient lies a lot of research. It is likely that for the development of the first vaccine and clinical trials, much more time is needed.

VRC01 has shown a high potency. Should scientists succeed in developing an actual vaccine, it might be a cheap and highly effective way to prevent AIDS.

No comments:

Post a Comment