The topic we are covering for our audio project is a new molecule that will help manage DNA leaving a potential to end retroviruses such as HIV and cancers. Since Nicole and Charlie went over the main paper and what the researchers discovered, I decided I would look a little bit into how HIV affects the Body and DNA. This will give a little bit of background on the subject to help understand what the molecule is helping against.
On the surface membrane of all living cells are complex protein structures called "receptors". A receptor is often compared to a lock into which a specific key or "ligand" will fit. There are at least two receptors on T-lymphocytes to which the human immunodeficiency virus (HIV) sticks. The primary receptor, called "CD4", is shown on the right in the diagram. But a second receptor that loops through the cell membrane 7 times is critical for infection to occur.
HIV infection of a lymphocyte requires attachment of the virus to the cell membrane through both of these "ligand-receptor" links. In cells whose "7-transmembrane receptor" is different, the HIV "key" no longer matches the lymphocyte "lock" and attachment is incomplete. Those cells may avoid infection by HIV.
Tight attachment of the viral particle to receptors on the lymphocyte membrane enables fusion with the cell membrane. The viral contents, including viral RNA then empty into the cell's cytoplasm.
Like other viruses that infect human cells, HIV commandeers the host's machinery to make multiple copies of itself.
An enzyme (protein) that's part of the human immunodefficiency virus reads the sequence of viral RNA nucleic acids that have entered the host cell and transcribes the sequence into a complementary DNA sequence. That enzyme is called "reverse transcriptase" . Without reverse transcriptase, the viral genome couldn't become incorporated into the host cell, and couldn't reproduce.
Reverse transcriptase sometimes makes mistakes reading the RNA sequence. The result is that not all viruses produced in a single infected cell are alike. Instead, they end up with a variety of subtle molecular differences in their surface coat and enzymes. Vaccines, which induce the production of antibodies that recognize and binding to very specific viral surface molecules, are an unlikely player in fighting HIV, because throughout infection, HIV surface molecules are continually changing.
The first major class of drugs found useful in slowing HIV infections are collectively called "reverse transcriptase inhibitors". These include AZT, 3TC, d4T, ddc, and ddl that act by blocking the recoding of viral RNA into DNA. The chameleon-like nature of HIV, however, limits their continued effectiveness.
Once the viral RNA has been reverse-transcribed into a strand of DNA, the DNA can then be integrated (inserted) into the DNA of the lymphocyte. The virus has its own enzyme called "integrase" that facilitates incorporation of the viral DNA into the host cells DNA. The integrated DNA is called a provirus.As long as the lymphocyte is not activated or "turned-on", nothing happens to the viral DNA. But if the lymphocyte is activated, transcription of the viral DNA begins, resulting in the production of multiple copies of viral RNA. This RNA codes for the production of the viral proteins and enzymes (translation) and will also be packaged later as new viruses. There are only 9 genes in the HIV RNA. Those genes have the code necessary to produce structural proteins such as the viral envelope and core plus enzymes like reverse transcriptase, integrase, and a crucial enzyme called a protease.
When viral RNA is translated into a polypeptide sequence, that sequence is assembled in a long chain that includes several individual proteins (reverse transcriptase, protease, integrase). Before these enzymes become functional, they must be cut from the longer polypeptide chain. Viral protease cuts the long chain into its individual enzyme components which then facilitate the production of new viruses.Inhibitors of this viral protease can be used to fight HIV infection. By blocking the ability of the protease to cleave the viral polypeptide into functional enzymes, protease inhibitors interfere with continued infection.
Mutations enable HIV to avoid treatments that involve only one drug, so there is growing use of multiple-drug therapies in which both a protease inhibitor AND a reverse transcript inhibitor are combined.
Finally, viral RNA and associated proteins are packaged and released from the lymphocyte surface, taking with them a swatch of lymphocyte membrane containing viral surface proteins. These proteins will then bind to the receptors on other immune cells facilitating continued infection.
Budding viruses are often exactly like the original particle that initially infected the host. In the case of HIV, however, the resulting viruses exhibit a range of variations which makes treatment difficult.
Wednesday, March 14, 2012
HIV infects more than 33 million people worldwide. Thanks to current prevention measures, such as certain tests that detect HIV early on and new antiretroviral drugs that can control the virus for decades, the infection with the virus that causes AIDS is no longer a death sentence. However, use of antiviral drugs for a lifetime raises questions of cost, side effects, drug resistance, and ultimate lifespan. Current research areas include trying to find a way to flush hidden HIV from cells to changing out a patient’s own immune systems cells, making them resistant to HIV, and then putting the cells back in the patient’s body. Plus, early human trials of vaccines designed to prevent or treat the infection has since shown to be disappointing. The greatest challenge for researchers to overcome is the fact that HIV is a provirus that is integrated into the DNA of a host cell, where it has the potential to remain latent or eventually reactivate. In fact, only one competent provirus in one tissue could reseed the entire infection after a vaccine has been applied.
The current focus of our audio project is to detail a current study expected to be a revolutionary step in the process of potentially finding a cure for HIV. Chemists at the University of Texas at Austin have recently published an article titled “A sequence-specific threading tetra-intercalator with an extremely slow dissociation rate constant” in Nature Chemistry (2011), which detailed the synthesis of a molecule with the ability to tangle itself inside the DNA double helix for an astonishing sixteen days before the DNA liberates itself. The synthesis of this molecule is an important step in the creation of drugs that can directly go after rogue DNA. This drug would be revolutionary in the treatment of genetic diseases, cancer, and retroviruses such as HIV. Specifically, the molecule developed utilizes “electron deficient aromatic intercalating units connected “head-to-tail” by flexible linking chains that slide back and forth through the DNA helix, analogous to how a snake would climb a ladder (according to Dr. Iverson, head researcher on the project).” Dr. Iverson’s lab is currently examining the relatively long lifetime of this class of molecule when bound to the DNA double helix, as well as examination into the mechanism by which the binding site is recognized among long stretches of unrecognizable DNA. The researcher’s ultimate goal is to control DNA binding duration and specificity sufficient gene expression in a predictable fashion.
The original research artricle can be found at Nature Chemistry
The original research artricle can be found at Nature Chemistry
Tuesday, March 13, 2012
Do you think that your childhood and high school experience would have been different if a genetic test had told you that you were predisposed to be an elite athlete? Do you think that your parents would have pressured you or pushed you to play certain sports in hope for a college scholarship or even a chance of playing professionally? There is actually a company called Atlas Sports Genetics that will test a child’s or adolescent’s genetics to determine if they have a gene that they claim plays a role in becoming an elite athlete. Atlas Sports Genetics charges 169 dollars for the test that will tell what type of sports/athletics your child is best suited for. The gene that is being tested for is the ACTN3 gene and it’s R577X variant. If the results show 2 copies of the variant then it means that the child is predisposed to be good at endurance events, 1 copy of the variant means a predisposition for both endurance and sprint/power events, and no copies of the variants for spring/power events. I found this extremely interesting because no matter the results it says that your child has a predisposition to be an elite athlete in some type of event, whether it is a sprinting or endurance events. When in reality, we all cannot and are not obviously elite athletes. In my opinion, I think this is simply to make the customer happy. If you send back results saying that your child is not genetically cut out to be an athlete that isn’t going to make the consumer to happy. On the other hand, if you tell them that their kid is predisposed to be some elite athlete they will tell their friends and they will most likely get their child tested as well.
Also, I believe that there are some definite moral and ethical issues with this testing. First of all, the idea of a self-fulfilling prophecy. If a child is told they are going to be an elite athlete and then it turns out that they are not, they will be crushed. In addition, this genetic testing completely takes away the environmental factor. It disregards the years and years of hard work and dedication that elite athletes put into their training. Michael Jordan didn’t just walk onto a basketball court one day and was the greatest basketball player ever because of his genetics. He practiced everyday for years and years. Furthermore, Dr. John Mulvihill, a clinical geneticist at Oklahoma University, says that genes don’t completely determine your outcome. Environment and lifestyle must be taken into consideration as well. In addition, Beth Tarini M.D. at the University of Michigan says that people can have different proteins that make muscles contract faster; that people can have 2 copies of these proteins instead of one which would make them better at sports. However, she states that it is not an absolute prediction, it is just a small predisposition, that work ethic must also be taken into consideration. I think that genetic testing like this is extremely interesting and has some credibility, but must be taken with some skepticism because there are many other factors to take into consideration, more research is needed to completely confirm the validity of these genetic tests.