Sunday, September 29, 2013

HIV Toolbox

Greetings

    In my last 2 blog posts, I have been talking about how hard the researchers are trying to develop a vaccine (includes both humoral and cellular immunity based vaccines). Though many approaches have failed to demonstrate a high level protection, and the scientists have reached a point of frustration, we have reached a time scale where, we are on the verge of development of novel strategies. HIV is probably one of those pathogen, that has defied the science, with the challenge still up in the air for anyone willing to catch it.

Fig 1: HIV intervention
   HIV-1 is intervened by several different approaches (Often referred vaguely in literature as the HIV toolbox). This has been an ever expanding list and there has been a great deal of progress in the existing category. The list shown in Fig 1, is by no means a complete data but, at least on the day of writing serve a backbone.

    In the last couple of weeks there has been some remarkable papers in this field, and i just want to put a very brief summary of these, as most of the ideas pertaining to these, I have discussed somewhere in my previous posts.

      bnAb (Broadly neutralizing Antibodies), has come up as a great deal of interest, especially in case of HIV and Influenza, where there is too much of antigenic variation, to attack using a single type of antibody. One of the well studied antibody is 4E10, is probably the neutralizing antibody with maximum spectrum binding known, recognizing a highly conserved epitope in the membrane-proximal region of gp41. Another well studied is b12 which overlaps the CD4 receptor-binding site (CD4bs) on gp120. Now the researchers from The Scripps Research Institute (TSRI) have shown that the 4E10, which has been of great promise, is also reactive against self antigens (Probably through cross reaction), whereas b12 is not. David Nemazee, a senior author said. "It's still possible that we could safely elicit the 4E10-like antibody in order to protect against HIV, We just have to think about how to generate the best antibodies without causing other problems. We have a lot of questions. And now we have a good model to help us answer them". Source

Fig 2: Ciclopirox
Source
      A yet another study has to do with, serendipitous observation that ciclopirox, used as an anti- fungal for treating skin infections can also attack HIV. The study looked at the ability of 2 well used pharmacological drugs- topical antifungal ciclopirox and the iron chelator deferiprone, for their effect on apoptosis in HIV-infected H9 cells and in peripheral blood mononuclear cells infected with clinical HIV-1 isolates. HIV delays or blocks the cellular apoptotic program, which seems to be reactivated in this case. The evidence comes form the activation markers- caspase-3 activation, poly(ADP-ribose) polymerase proteolysis, DNA degradation, and apoptotic cell morphology of infected cells. However, the best part of this study is that there was no viral re-emergence was observed even 12 weeks after drug cessation, suggesting elimination of the proviral reservoir.

Fig 3: DAVEI activity
Source
     The third paper that was published earlier, is based on a lab construct microbicide referred as "DAVEI" (Dual Action Virolytic Entry Inhibitor). This is a chimeric recombinant protein, constructed of a fusion of the lectin cyanovirin-N (CVN) and the gp41 membrane-proximal external region (MPER) peptide with a variable-length (Gly4Ser)x linker (where x is 4 or 8) between the C terminus of the former and N terminus of the latter. Its long been testified based on earlier studies that the HIV fusion machinery is based on the idea of Spring load mechanism (Thats the basis of fusion inhibitors). The MPER component is is itself a small piece of the fusion machinery and interacts strongly with viral membranes. Cyanovirin, binds to the sugar coating of the protein spike. The binding of virus, gets the virus to be signaled that it has attached to a cell, and hence releases genetic material, where in reality there is no cell. This leaks the genes out, which is harmless. Prrr.. Tricked the virus!!!   Chaiken said "DAVEI and other new-generation virolytic inactivators open up an important opportunity to develop a topical microbicide to block the transmission of HIV, and at the same time provide lead ideas to discover treatment strategies for people who are already infected, Our hope is that determining the structural driving forces of both inhibitors and viral entry machinery that enable spike inactivation will help to advance molecular designs with increased power, specificity and clinical potential for both prevention and treatment" Source

ResearchBlogging.org
Doyle-Cooper C, Hudson KE, Cooper AB, Ota T, Skog P, Dawson PE, Zwick MB, Schief WR, Burton DR, & Nemazee D (2013). Immune Tolerance Negatively Regulates B Cells in Knock-In Mice Expressing Broadly Neutralizing HIV Antibody 4E10. Journal of immunology (Baltimore, Md. : 1950), 191 (6), 3186-91 PMID: 23940276

Hanauske-Abel, Hartmut M. (2013-09-23) Drug-Induced Reactivation of Apoptosis Abrogates HIV-1 Infection. , 8(9), e74414. DOI: 10.1371/journal.pone.0074414

Contarino M, Bastian AR, Kalyana Sundaram RV, McFadden K, Duffy C, Gangupomu V, Baker M, Abrams C, & Chaiken I (2013). Chimeric Cyanovirin-MPER Recombinantly Engineered Proteins Cause Cell-Free Virolysis of HIV-1. Antimicrobial agents and chemotherapy, 57 (10), 4743-50 PMID: 23856780

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