Saturday, September 27, 2008 - 06:03
One of the holy grails of modern medicine is the development of a vaccine against HIV, the virus that causes AIDs. An obstacle to attaining this goal has been the difficulty in stimulating the immune system to make it produce the right kinds of antibodies. A recent finding in Science describes a gene that controls production of these antibodies and may provide insights to the development of an effective vaccine. (1). Antibodies are special kinds of proteins that bind to things, often very tightly. If they bind to the right molecules, they can prevent viruses from infecting cells and target those viruses for destruction by the immune system. These antibodies are called "neutralizing antibodies."
Many vaccines work by encouraging the immune system to produce neutralizing antibodies. But sometimes the immune system doesn't cooperate. As with the production of any protein, the ability of the immune system to do it's job and protect us, depends on genetics. In the paper by Santiago, et. al., the authors discuss the properties of a mouse gene called Rfv3 (1). It's been known for awhile that Rfv3 can protect mice from certain retroviruses and inactivating the gene makes mice susceptible. Until this study, however, it wasn't known that Rfv3 has another identity. Rfv3, it turns out, is really Apobec3. At this point, you're probably thinking "huh? and what does that have to do with the price of tea in China?" Well, Santiago's group found two very important results. 1. That Rfv3 really is Apobec3. (I'll explain why this is important in a moment.) 2. That Rfv3 is required for the production of antibodies that will neutralize a retrovirus called FV. FV stands for Friend Virus and this is not because the virus is friendly. Why is this so cool? Well, this is a big "if," but if we can make neutralizing antibodies, we can make a vaccine. FV is a retrovirus that infects mice, not humans, but the things we might be able to apply the things that we learn, about resistance to FV in mice, to HIV infections in humans. The take home message is that knowing the identity of a gene that controls the ability to make neutralizing antibodies to FV is very helpful. Okay, but why is knowing the secret identity of Rfv3 important? What do we care about mice and their ability to recover from a viral infection anyway? We care because of evolution. Mice and men are very similar and the things we learn about mice can be applied to humans. Mice are the E. coli of immunology. At first, I was a bit puzzled about the importance of Apobec3. I looked up the gene and found that in humans, there is a whole family of seven APOBEC genes and the proteins they make are known to edit RNA (2). That is, the APOBEC proteins bind to RNA sequences and remove an amino group from cytidines, changing the C's to uracils. This property, it turns out really messes with retrotransposons and retroviruses. You can image right, if you take a sentence in a paragraph and change every "e" to another letter, the meaning might change? Well, changing a large fraction of the letters in the virus RNA prevents these viruses and retro elements from making their proteins properly and severely disrupts the viral life cycle. I could see how messing with a viral genome would be a problem for the virus, but what does this have to do with neutralizing antibodies? This answer comes from evolution. Quoting Santiago and another paper by Muramatsu (3), the protein we're interested in:
*Note: nothing in this image is drawn to scale.
.. is expressed in B cells and is evolutionarily related to activation-induced deaminase, an enzyme that controls somatic hypermutation and class-switch recombination in these cells.Somatic hypermutation is a kind of a scary phrase. It describes a process where some of the bases in DNA get modified by special enzymes, thus causing mutations. This isn't a random process. It happens mostly in certain regions of antibody genes in B cells. This is helpful in the immune response because some of the antibodies that get produced will bind to viral proteins more tightly and - you guessed it - be more effective at neutralizing the virus. Tying this back to the human proteins, I used Blink to find out which human proteins are most similar to the mouse Apobec3 protein and I found that APOBEC3F is the closest. Even better, APOBEC3F is KNOWN to cause mutations in HIV DNA and block it's activity (4). Maybe APOBEC3F also has something to do with mutating antibody genes. What's the next step? Santiago has made some mice with mutations in the Apobec3 gene. My guess is that they'll take a look now at the antibody genes in B cells and see if the process of somatic hypermutation has been affected. Reference
- M. L. Santiago, M. Montano, R. Benitez, R. J. Messer, W. Yonemoto, B. Chesebro, K. J. Hasenkrug, W. C. Greene (2008). Apobec3 Encodes Rfv3, a Gene Influencing Neutralizing Antibody Control of Retrovirus Infection Science, 321 (5894), 1343-1346 DOI: 10.1126/science.1161121
- Y. Dang, X. Wang, W. J. Esselman, Y.-H. Zheng (2006). Identification of APOBEC3DE as Another Antiretroviral Factor from the Human APOBEC Family Journal of Virology, 80 (21), 10522-10533 DOI: 10.1128/JVI.01123-06
- M MURAMATSU (2000). Class Switch Recombination and Hypermutation Require Activation-Induced Cytidine Deaminase (AID), a Potential RNA Editing Enzyme Cell, 102 (5), 553-563 DOI: 10.1016/S0092-8674(00)00078-7
- A long list of papers describing how APOBECG and APOBECF induce mutations in HIV genomic DNA