Brian Krueger is the owner, creator and coder of LabSpaces by night and Next Generation Sequencer by day. He is currently the Director of Genomic Analysis and Technical Operations for the Institute for Genomic Medicine at Columbia University Medical Center. In his blog you will find articles about technology, molecular biology, and editorial comments on the current state of science on the internet.
My posts are presented as opinion and commentary and do not represent the views of LabSpaces Productions, LLC, my employer, or my educational institution.
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One of the biggest problems facing the eradication of hard to kill viruses such as HIV is that viruses mutate readily. A standard technique for creating lasting immunity against viruses is the creation of vaccines. These have been used for years to eradicate a multitude of viruses. There are three standard types of vaccines that have been used in the past. There are attenuated viral vaccines which use a weakened form of the virus to challenge the immune system, killed virus vaccines which use dead viral particles to trigger the immune system, and finally there are peptide vaccines which use the expression of a specific viral protein to trigger the immune system. Although these approaches work readily for many viruses, in the case of a small subset of human pathogens, such as for HIV, these techniques cannot be used to create lasting immunity. In these cases, the virus mutates so readily that any immunity gained is quickly lost because the immune system can no longer recognize the virus.
Over the years we have become increasingly innovative in our strategies for attacking the HIV virus. We have developed specific small molecule inhibitors of viral proteins that work very well in the short term. One of the first of these was the nucleoside mimic AZT. This drug worked because it “looks” a lot like the DNA base Thymine and inhibits the viral polymerase, or protein machine responsible for coding DNA strands. The only problem is that over time, the virus mutated to become resistant to AZT therapy. Now AZT must be used in conjunction with one of the many other HIV therapies that are used as a part of highly active anti-retroviral therapy (HAART). There are currently 6 classes of drugs that target specific HIV proteins, all of which are used in different combinations as a part of HAART to limit HIV resistance to any one of the drugs. These classes include the Nucleoside and nucleotide reverse transcriptase inhibitors (NRTI), Non-nucleoside reverse transcriptase inhibitors (NNRTI), Integrase inhibitors, Entry inhibitors, Maturation inhibitors, and Protease inhibitors. Because mutation is at the crux of HIV resistance to all of the current strategies used to combat the virus, it seems logical to target proteins that the virus has no control over and which are not subject to viral mutation.
Many viruses rely on specific host proteins to replicate and mature. HIV is no exception and it associates with a variety of host proteins. Of these proteins, Positive Transcription Elongation Factor b (P-TEFb) can be considered the ultimate gate keeper and is absolutely required for HIV survival. In the absence of this protein, HIV replication is undetectable within the cell. However, HIV produces a protein, Tat, which binds to and specifically recruits P-TEFb to itself to activate a 1,000-fold increase in viral replication. Loss of either P-TEFb or Tat results in the death of the virus. Additionally, there are very good specific inhibitors of P-TEFb available. So why hasn’t a P-TEFb therapy been used to cure HIV? P-TEFb is also one of the single most important proteins in your cells. It is one of the key regulators of mRNA transcription, which controls the production of every protein in your body. Complete inhibition of P-TEFb results in cell death within 8 hours, because it prevents your cells from creating the messages required for producing essential proteins. To use P-TEFb inhibition as a viable therapy against HIV, a drug must be developed that specifically inhibits the form of the protein taken over by HIV.
Last month, a paper was published detailing the crystal structure of HIV Tat bound to P-TEFb. Crystal structures are exact three dimensional models of protein complexes that show scientists where atoms line up in a protein structure. These shapes can be used by biochemists and drug designers to create molecules that fit specifically in the nooks and crannies of the proteins and affect the protein’s ability to function. This work shows that the crystal structure of P-TEFb bound to Tat is different than the crystal structure of free normal functioning P-TEFb meaning that new drugs can be developed to specifically inhibit the virally hijacked form of P-TEFb while leaving the virus free form of the protein to go about its normal activities in the cell. ### The paper: T. Tahirov, et al. 2010. Crystal structure of HIV-1 Tat complexed with human P-TEFb. Nature http://www.nature.com/nature/journal/v465/n7299/full/nature09131.html Disclosure: Brian Krueger completed his PhD in the lab that co-authored this study. He played no direct role in the publication of this paper.
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