DNA vaccine delivery system and Nef- Achilles heel

Greetings

     Recently had an argument (Not furious!!!) with one of my friends about topics chosen to blog and how it effects the readership. Our conclusion was, that if you write about very broad topics, in the way of a summary (Kind of blog review), the chances that the page will be read is high, than when you talk about a single article. This is simply because, most of the readers, reach a blog site, through search engines via keywords. And, Keywords are more in review compared to single paper talk. Its kind of the same scenario, about impact factor, used for journals.

    Before i get into the topic of the post, I want to make some points clear, especially for those who believe too much on impact factor for journals. The impact factor depends on number of citations a paper has received (Within 2 years of publication). For details on how it is calculated go here. As might be expected, journals that focus more on review will be cited more easily. This is possibly because, the matter is sometimes more digestible and well explained in comparison to the original papers. So they get easily cited. Moreover, impact factor is derived from the cited papers in a journal, and non cited are ignored. This means even if one paper is cited several times, but the rest is crap, you still get a pretty good impact factor.

   That ends the first part, that I wanted to say since a long time. The second part of the blog comes with two papers.

Photo 1: BD Soluvia 

Microneedle device

Source

       The first study has to do with vaccines. Perhaps, what is the best strategy of vaccination? Live attenuated, Killed, Sub-component? Or the more sophisticated approach of DNA / RNA vaccines? While all the traditional vaccines have been good at some point, the long term effects have been variable. Many a times, vaccines has to be given repeatedly. That's where the idea of DNA vaccines come form. The recent success of mRNA vaccines against Influenza has brought in new hope. Read the story here.

    But more recently, the technique of delivery has also been researched under new light. for example the influenza vaccine delivery system. the 2 licensed mode of influenza vaccine delivery include intradermal vaccines using a microinjection system (BD Soluvia) and intranasal vaccines FluMist. That's one way of looking at it.

     Now what if i told you that scientists have one more possible armory, that combines the best of 2 worlds. On one way you have the potential DNA vaccine and on the other hand the elegance of a delivery system. That's exactly what the story is about. Researchers from MIT has developed a new type of vaccine-delivery film that holds promise for improving the effectiveness of DNA vaccines. This is a polymer film that gradually releases DNA coding for viral proteins. In a sense this polymer acts as an adjuvant that gives a controlled release. Given the promise of DNA vaccines this should be of great value. These polymer films are implanted under the skin using microneedles that penetrate about half a millimeter into the skin — deep enough to deliver the DNA to immune cells in the epidermis, but not deep enough to cause pain in the nerve endings of the dermis. Irvine (a senior author in this paper) says. “If you're making a protein vaccine, every protein has its little quirks, and there are manufacturing issues that have to be solved to scale it up to humans. If you had a DNA platform, the DNA is going to behave the same no matter what antigen it’s encoding”. For source and more information go here.

Fig 1: HIV-Nef. Source

   The 2nd paper is by Smithgall etal. The paper is titled "Effector Kinase Coupling Enables High-Throughput Screens for Direct HIV-1 Nef Antagonists with Antiretroviral Activity". The paper revolves aroud the factor nef, a culprit involved with HIV infections. Nef stands for Negative Regulatory Factor, which is expressed by most of the members of lentivirus group. The function is to increase the survival of infected T cells and for destruction of non-infected T cells (probably thorugh apoptosis). It accelerates the endocytosis of MHC class I molecules through the phosphofurin acidic cluster sorting protein 1 (PACS1)/phosphatidylinositol 3-kinase (PI3K)-dependent activation of ADP ribosylation factor 6 (ARF6)-mediated endocytosis. Reference. The point is, Nef is a key factor is bypassing the immune system control.

    The researchers were able to track the kinetics of nef by tagging with an enzyme Hck, which is activated by Nef in HIV-infected cells. High throughput drug screen was carried (with about 250000 compounds). A compound called B9 was identified, which inhibited the Nef activity strongly. In a series of experiment, they were able to pin down a important observation. B9 could prevent Nef dimerisation impairing its function in the viral replication process. Dr. Smithgall said "This pocket where B9 binds to Nef and where Nef forms a dimer indicates it's a hot spot, or Achilles heel, that could represent a new target for HIV drugs". For source go here.

Peter C. DeMuth, Younjin Min, Bonnie Huang, Joshua A. Kramer, Andrew D. Miller, Dan H. Barouch, Paula T. Hammond & Darrell J. Irvine (2013). Polymer multilayer tattooing for enhanced DNA vaccination. NATURE MATERIALS : doi:10.1038/nmat3550

Emert-Sedlak LA, Narute P, Shu ST, Poe JA, Shi H, Yanamala N, Alvarado JJ, Lazo JS, Yeh JI, Johnston PA, & Smithgall TE (2013). Effector Kinase Coupling Enables High-Throughput Screens for Direct HIV-1 Nef Antagonists with Antiretroviral Activity. Chemistry & biology, 20 (1), 82-91 PMID: 23352142

Further Reading:

1. Stanley A. Plotkin. Vaccines: the Fourth Century. Clin Vaccine Immunol. 2009 Dec;16(12): 1709-19. Link

2. John L Foster and J Victor Garcia. HIV-1 Nef: at the crossroads. Retrovirology 2008, 5:84. Link