|Antibody binding HIV. Peter Kwong, NIH|
Yesterday I posted about how HIV antibodies are made. But why are they important? More specifically - why is the recent work on broadly neutralizing antibodies important?
Antibodies are produced against cell surface proteins, the portions of the infecting agent visible to immune cells. The problem thus far with HIV is the broad range of cell surface proteins expressed by the various strains currently infecting the human population, as well as the potential mutations to come. However, broadly neutralizing antibodies, though rare, have been identified in the blood of HIV-infected patients. They bind and affect portions of the cell surface that remain relatively constant among HIV strains.
Read more about the challenges and promise of broadly neutralizing antibodies in HIV vaccine development below the break.
The human immunodeficiency virus (HIV) is a tricky pathogen that eludes the immune system by undergoing continuous mutation when it replicates inside human cells. These mutations also make it a difficult pathogen to vaccinate against. Vaccines trigger the immune system to produce protections against infection by spurring pre-emptive antibody production, which eliminates the pathogen when it first infects rather than several days into an infection after the immune system has had time to recognize and replicate the needed cells and proteins. These few days of immune system mechanics is all HIV needs to make itself at home inside immune cells and become a lifelong burden.
Antibodies are produced against cell surface proteins, the portions of the infecting agent visible to immune cells. The problem thus far with HIV is the broad range of cell surface proteins expressed by the various strains currently infecting the human population, as well as the potential mutations to come. The most promising vaccine candidate to date (July 2010) was found in clinical trials to only be effective for less than one-third of affected individuals. This is hardly the result needed with a vaccine.
However, scientists have discovered naturally occurring antibodies against HIV that have a broad effect on various strains – broadly neutralizing antibodies. The antibodies are rare, but have been identified in the blood of HIV-infected patients. They bind and affect portions of the cell surface that remain relatively constant among HIV strains, such as the CD4 binding site (glycoprotein gp120), a protein that binds the CD4 receptor on T cells, allowing the virus to infect the cells. Blocking this receptor blocks infection, essentially neutralizing the virus. Previous work (Sun et al. 2008) had focused on broadly neutralizing antibodies against the structural elements of viral gp41, the protein responsible for HIV fusion and cell entry after binding.
On July 8, 2010, the National Institutes of Health (NIH) announced that one of their research groups had discovered a pair of broadly neutralizing antibodies that are effective against 90 percent of current HIV strains – VRC01 and VRC02. The researchers tested the antibodies with human cells to determine whether they prevent HIV infection in the lab. These HIV antibodies are the most promising step towards a vaccine to date, and the scientists are hopeful that VRC01 and VRC02 may hold the key to developing a vaccine against HIV and preventing further spread of the associated acquired immune deficiency, AIDS.
The researchers are studying where and how the antibody binds, which in turn tells them about the binding habits of HIV and allows them to enhance the natural effects of the antibodies by designing vaccine components that exploit these mechanisms and cell surface features. A potential vaccine could coax the human body to make these antibodies and other factors that enhance their protections, preventing HIV from infecting T cells and greatly reducing the number of infections. Since 1981, HIV has been attributed to 25 million deaths.