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In the now decades-long battle against HIV and AIDS, researchers have been stymied by the virus’s ability to evade attacks by our immune system.
Normally, a cell that is infected by a pathogen displays on its surface characteristic pieces of the pathogen peptides, known as epitopes, which are then recognized by the body’s immune system and trigger immune responses. HIV-infected cells produce these epitopes, but because HIV mutates so readily, so do the epitopes, leading to an ongoing struggle between our immune system and HIV. Therefore, scientists have been eager to gain a better understanding of the process of epitope production in HIV-infected individuals in the hope that such knowledge could lead to ways to beat HIV at this game.
Recent work on the degradation of HIV proteins in infected cells has provided new insight into the process of HIV epitope presentation. This important research was conducted by a team at the Ragon Institute (a joint venture of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University), with contributions from Carl Kadie and myself at the eScience Group of Microsoft Research. The paper was published online in the Journal of Clinical Investigation (JCI) on May 9, 2011, and will appear in the June issue of JCI’s print publication.
The Ragon team, which was led by Sylvie Le Gall and included Estibaliz Lazaro, Pamela Stamegna, Shao Chong Zhang, Pauline Gourdain, Nicole Y. Lai, Mei Zhang, and Sergio A. Martinez, examined the stability of short HIV peptides in the cytosol of human cells. They discovered that the stability of these HIV-derived peptides is extremely variable: some degraded within seconds, while others remained largely intact after an hour.
The Ragon team observed that peptide stability is crucial to determining how much of the epitope will be displayed on the cell surface: the less peptide degradation in the cytosol, the more epitope will be present on the surface of an infected cell.
Carl and I then performed a computational analysis of the residues of 166 tested HIV peptides, looking for specific biochemical features that characterized stable and unstable peptides. This enabled us to identify multiple motifs or patterns that allow us to predict how stable or unstable a given epitope will be. A prediction tool based on our findings is available online.
So, what is the value in predicting epitope stability? To answer that question, we first need to know that some researchers believe HIV has both protective and non-protective epitopes. When infected cells are attacked by the immune system, protective epitopes force the virus to mutate into a version that will not survive, protecting an individual against chronic HIV infection. Non-protective epitopes, in contrast, do not induce a protective immune response. We also need to understand that epitopes are cross-reactive, which means that when the immune system learns to fight a specific epitope, it can also recognize and attack similar epitopes. Suppose, therefore, we know that HIV epitope X is protective but is also unstable. That means it won’t be produced in large quantities and thus will likely not be a successful target for an immune response. But if by using the results of our research we could identify an epitope X-prime that is cross-reactive to X but more stable, we could then develop a vaccine based on X-prime that would yield a strong immune response to both X-prime and X. This would enable the immune system to more effectively attack HIV-infected cells that express the X epitope and thereby weaken the virus.
Our collaboration with the Ragon Institute has uncovered a path that will better help us present pieces of HIV to activate the immune system and thus hopefully design an effective vaccine against HIV. It has been extremely productive and rewarding.
—David Heckerman, Senior Director, eScience Research Group, Microsoft Research
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