Conclusion

Herpesviridae is incredibly efficient at infecting humans and has evolved over time to adapt to any human defenses posed to it. It is a dangerous virus that burdens millions of people and, unfortunately, there is still not a cure. In order to find a cure for this adaptable, evolving disease research efforts must be bolstered and combined in new innovative ways. One of these ways is grid computing. It allows scientists from around the world to harness the computing power of thousands of computers to analyze and compare mass amounts of data on protein folding. The manner in which Herpes viral proteins fold determines their individual actions. The virus itself is made up of thousands of proteins and their actions determine how the virus infects and replicates. If the specific folding of each protein is determined, medicines can be developed to interrupt their actions. Grid computing will allow for this. This collaboration effort will move Herpesviridae research towards more effective treatments and eventually a cure.

Our group has realized the importance of grid computing and contributed to the effort by joining to the Rosetta@home grid computing project powered by BOINC. Over the last few months we have contributed 17,432 points by joining the grid.

"Molecular Evolution of the γ-Herpersvirinae" Questions

1. Why is the elevated mutation rate in herpes viruses a positive aspect for this phylogenetic study?

Mutation is a source of genetic variation and when it acts with selection it is a major force of evolution. The elevated mutation rate is important in this study because it allows them to follow the evolution of this virus and build a phylogenetic tree based on evolutionary relationships.

2. What do the eight core genes code for (page 422)? Why did this study choose to focus on these genes?

The eight core genes are 06, 07, 08, 09, 25, 29, 44, and 46.

06- encoding the major DNA binding protein

07- DNA packaging function

08- virion glycoprotein B

09- catalytic subunit of DNA polymerase

25- major capsid protein

29- DNA-packaging protein

44- DNA helicase

46- uracil-DNA glycosylase

They chose these genes to study because they are sufficiently well conserved over the whole family. This allowed adequate amino-acid sequence alignments when looking at phylogenic relationships.

3. Herpes viruses tend to “capture” genes from their host genomes and incorporate them into their own genomes. That said, explain the relationships you see in the phylogenies in Figure 4 on page 427.

The EBV, HPV, and HVS viruses incorporate the host genome into their own during the infection process. By capturing a healthy cell's machinery, the viruses can efficiently transcribe proteins necessary to the infection process and also become less prone to immune attack by incorporating non-foreign genes into their genome. The phylogenies in figure 4 compare IL-10 and DHFR genes in organismal cells and in viruses. IL-10 is a protein involved in cytokine synthesis and when expressed, can reduce inflammation and the immune response. This has obvious advantages in a virus. DHFR is a gene used in purine production and makes for efficient transcription and translation. If incorporated, the virus will more readily proliferate. With this knowledge, the two genes were examined in a variety of organisms, including humans, and comparing them to the viral genes. The phylogenies in figure 4 show a progression in genome complexity, with the virus first incorporating genes in more simple organisms and eventually moving to incorporation of the human genes. The viral IL-10 and DHFR are closely related to the human genes, showing the viruses success in infecting humans. It is rare for a virus to show such a similarity to human genes, but EBV, HPV, and HVS have evolved in such a way to be able to fend off the human immune system and pirate its genetic machinery for more efficient proliferation.

4. Part 5, beginning on page 431, discusses genetic characteristics of two Epstein-Barr viral strains. On page 432, the author explains that there are four genes involved but that only two combinations of their alleles (i.e. four haplotypes) predominate. What do we call this evolutionary phenomenon? Do these combinations have any evolutionary advantage?

This is an example of linkage disequilibrium. This is evidenced by the fact that there are only two combinations of alleles (or four haplotypes) because the genes are linked and only inherited together. This offers an evolutionary advantage because the combinations of genes that are most infective are selected for and are going towards fixation.

5. Why might it be important to study protein folding in these viruses?

The folding of a protein determines its shape. Its shape determines whether it can be catalyzed by an enzyme to participate in a reaction, or if the protein is an enzyme, whether it can catalyze a reaction. Proteins control all of the major functions in a cell or virus from replication of genetic material to the actual infection process. If a protein vital to Herpes virus’ function is isolated and its folding is determined, steps can be taken to inhibit its folding or catalysis and effectively stop the virus from proliferating.

6. The last paragraph of this paper states that EBV genes respond to allele frequencies of MHC genes in human populations. How would human MHC genes (and changes in their frequencies) act as a selection pressure on viral gene frequencies?

MHC genes express protein fragments on the cell walls of immune cells (natural killer and macrophages). These protein fragments are often processed proteins from a bacterium or virus that were recognized as foreign. The MHC fragments allow immune cells to recognize these foreign invaders if they happen to reappear in the body. After recognition they can attack and eradicate them.

The EBV virus frequency will gradually decrease as its proteins are recognized and expressed by MHC molecules. The immune system will become more efficient in attacking them as they become more common in the body. As a result, EBV must incorporate healthy cellular genes/proteins from the organism it is attacking to essentially hide from the immune system. If a virus incorporates non-foreign genes, the immune system will not recognize and attack it. This leaves two evolutionary options for EBV, either gradually decrease in frequency as the immune system becomes completely proficient in attacking it, or diverge by incorporating new genes and "hiding" from the immune system.

Interview Reflection

1. Describe your feelings about or response to the interview.

We felt the interview went very well. Dr. Read was very easy to talk to and helped us to better understand his research and herpes research in general. The interview also taught us more about the general field of research; he spoke about research in several different areas and also about his own life and what led him to research. It was interesting for me to hear about his path that led him to where he is today. My feelings about the interview, personally, were that it really helped me to see the research side of science and see more what it is like to have a career in that field. I have learned a lot about research and the research process, but it was a very good experience to actually meet and talk with someone who chose to pursue this route as their career.
2. What changes occurred for you as a result of your interview?

A change that occurred was that after the interview I knew more about what benefits our grid computing project could have. Dr. Read spoke at length about the herpes virus and what benefits come from using it in research, and it was good to learn what benefits our project could have.

3. Did anything about the interview disturb you?

I wouldn't say that anything about the interview disturbed me. Some surprises I had were that Dr. Read had never before heard of grid computing or several of the treatments that we asked him about. This was a good thing in a way because it gave us the chance to explain grid computing to him and to get his initial reaction to the concept. We also explained some of the treatments he had not been aware of. Since he is in the research field and not medicine, I suppose it is not all that surprising that he was not aware of some treatments. After we explained the treatments we had heard of, it was interesting to hear his thoughts and analysis of their possible background and mechanism.
4. Describe the connections you found between the interview and your research & classwork.

The connection we found was that we got to see a research facility and meet a researcher who is probably very similar to the one heading our grid computing project. It was great to see and learn about where the research is being done and what direction it is heading in in the future. I really enjoyed seeing this side of science and it is good to know about the scientists who will benefit from this project.

Interview with Dr. G. Sullivan Read

On February 23rd, the three of us interviewed Dr. G. Sullivan Read, who works in herpes virus research at the University of Missouri-Kansas City. During the interview, Dr. Read discussed with us many things involving virus research such as his reasons for why grid computing could be effective, reasons for studying viruses, the path that led him to researching the herpes virus, and several other topics.

Dr. Read had never heard of grid computing before our interview, but once we explained the concept to him, he was quick to say how it could greatly contribute to the field of herpes research and the research field of science overall. This discussion segued into the explanation of why people study viruses at all. Initially we discussed the obvious reasons that people study viruses, in particular the diseases caused by them and the efforts scientists go to to develop a vaccine against them. Dr. Read also discussed viruses as a tool used to research the basic function of cells. Viruses, he said, are a way to implement the same genes into a cell population as a way to get a group of cells to do the same thing at the same time. These viruses have genes that can be implemented into the host cells, causing them to do the same thing at the same time. A population of cells acting in unison can be very helpful to research as a way of studying cell processes. He also mentioned the usefulness in using viruses to study protein folding. Using a virus to cause cells to make a viral protein, allowing the researcher to study not only the cell processes involved in protein folding but also the viral protein itself in efforts to develop an anti-viral medication. Dr. Read also mentioned the connection between studying the basic science of a virus and the application of it in applied sciences. A researcher in basic sciences often makes discoveries that are applicable and important in the area of applied sciences, such as medical research.

Dr. Read also told his story and how he ended up in herpes research. He was originally planning on being an elementary particle physicist. After beginning work towards a Ph.D. in that subject, he found many aspects of biology that he liked. He found that he was more suited, personally, to the field of biology and that it was a better fit for his personal and family life, and that he liked the university setting better than the lab setting, leading him to switch his Ph.D. studies to biophysics. He ended up in herpes research due to a mentor he found when he was younger who was in herpes research. He described his advisor as a cool guy who was fun to be around and was excited about what he was doing, and he happened to be studying herpes. Dr. Read said he has been studying herpes ever since, and that is a a fascinating virus and it is fun to do the work he does with the virus.

Dr. Read’s research is centered on the basics of what goes on inside a cell affected by herpes and the viral proteins that control these cell’s activities. His studies could possibly lead to anti-viral compounds based on the discovery of how different viral proteins work. Anti-viral compounds must be able to work against the virus and against the cells infected by the virus without affecting the surrounding unaffected cells. He says this is more difficult than developing a drug against cells infected by bacteria. Viruses use the cellular transcription apparatus, DNA replication apparatus, and other cellular enzymes to synthesize the viral proteins. So, if a drug affects viral transcription then it will probably affect cellular transcription as well. Because of this, it is key to be able to inhibit the replication of the virus in infected cells while not affecting uninfected cells in the body. To accomplish this, he says you must figure out how the viral proteins work, because these give you targets that can be inhibited by drugs that are specific against them. He explained to us that some anti-viral compounds act by interrupting the polymerization of viral proteins. A specific drug, Acyclovir, is useful because the sugar in its chemical structure is acyclic, as opposed to the cyclic sugars in DNA. These acyclic sugar does not allow anything to be added on to the chain after it, thereby inhibiting the addition of another base and halting viral DNA replication.

Overall, the interview was helped each of us to learn a lot more about the basic virology of the herpes simplex virus, the reasons and importance for studying viruses in general, and the methods of application for virus research. Dr. Read was very friendly, outgoing, and helpful in helping us understand his research and virus research in general.

Thanks to Dr. G. Sullivan Read for his willingness to discuss his research with us and help us better understand the basics behind the infectiveness of the herpes simplex virus.

Introduction and Background

This blog will track the progress of our participation in a grid computing project searching for new treatments of Herpes Simplex and will offer some information on the virus. Grid computing is a combination of computing power from a large number of computers, spread out geographically, and all aimed at completing a single task, which in our case is compiling data on the Herpes virus, analyzing it, and looking for specific patterns that may produce a cure. This method is relatively new in the scientific world. It allows for a mass amount of data to be cheaply analyzed, while providing collaboration between scientists from around the globe. Grid computing is certainly a large part of the future for all sciences.

For those that do not know, Herpes comes in two forms: Herpes Simplex I (HSV-I) and Herpes Simplex II (HSV-II). Both fall under the family, Herpesvirdae, a class of DNA viruses. HSV-I infection is normally manifested on the lips, mouth, face, and eyes. It causes lesions commonly known as cold sores on the epidermis and conjunctiva in the eye. It is transmitted through saliva, and children are most susceptible, as adults generally have developed immunity. HSV-II infection generally manifests itself as s

ores and ulcers on or around the genitalia. It is sexually transmitted (www.medlineplus.com).

Unfortunately, there is not a method to eradicate herpes from an infected persons body. Herpes lies dormant in the neural ganglia. Specifically, HSV-I generally resides in the trigeminal ganglia, while HSV-II is commonly found in the sacral ganglia. This type of infection is known as latent. Latent infections often have recurring symptoms and are difficult to treat (http://pathmicro.med.sc.edu). With the help of grid computing, it is

our hope that this can be changed.