In the case of cell targeting, there is usually a defined cell region that a known protein can bind to, its binding site. Once these sites are confirmed, steps can be taken to attach immunogen proteins to them, mimicking the same structure that would allow binding to the binding site. This works, however, when the defined binding region is known and readily accessible by the protein. The problem with HIV-1 is that due to its high error-prone reverse transcriptase, the coding for this binding site or the region of the virus envelope frequently changes2,3.
This leads to the problem of accurately marking these sites and triggering them for destruction. Thus the researchers of this article have discovered an antibody protein that shows stable binding to the viral envelope, which can lead to engineering a vaccine, preventing viral infection.
SO WHATS THE PROTEIN AND WHAT MAKES IT SO GOOD AS A MARKER?
Well the protein discussed is actually an antibody, and it is apart of a large family of proteins called broadly neutralizing antibodies, or bnABs. Recently these antibodies have been shown to bind to the nuclear envelope of the HIV-1 virus and effectively neutralizing it. Binding the envelope is very important since the glycoprotein found on the envelope is the mechanism by which the virus particle gains entry to the target cell. If the glycoprotein can be changed or constricted in any way (i.e. binding to it), then the virus particle is hampered from entering the cell and causing infection1.
The problem is that these antibodies have mediocre binding potential due to the difficulty of binding to the conserved region on the viral envelope; with other proteins blocking the site as well as steric hindrance. However PG9, a unique bnAB, showed a stable and repetitive binding site conserved on the viral envelope. PG9 bound to the envelope in a way that was most curious, it bound with the trimers of the glycoprotein of the virus and formed a quaternary structure with the binding site. This type of binding leads to high stability, which was confirmed by the heat points recorded during the PG9-Envelope glycoprotein interaction1. Using different viral viewing methods, such as electron microscopy and crystal structures, the researchers were able to identify the sites that PG9 binds to. The research showed that there was a high affinity in binding between PG9 and the HIV-1 envelope glycoprotein. The PG9 antibody binds to two out of the three monomers of the envelope glycoprotein, a trimer complex. This dual binding is important but other antibodies have this characteristic as well, so what is it about PG9 that makes it better? The researchers found that PG9 has a second interaction site beside the three monomers of the envelope glycoprotein, a monomer on an adjacent glycoprotein. This three monomer binding complex that PG9 forms with the envelope glycoprotein has shown to be thermally stable and readily able to neutralize virus due to its interactions at the monomers of the glycoprotein4. By blocking these monomers, the overall integrity of the trimers in the glycoprotein is compromised, possibly leading to its inability to enter the cell.
Though these antibodies exhibit neutralizing effects on the virus particle, they are not a way of lowering infection. This mechanism of viral neutralization would have to take place before the virus propagates in the cell; it is only effective in preventing the onset of the virus5.
With this data, researchers are hoping that it can serve as some sort of template for vaccine design. The way it would work is that a protein designed or known to increase an immunogenic response would be engineered or “packaged” with similar structural elements of the PG9 protein. The PG9 antibody offers more than just a template for vaccines however, it can also be used to figure out the glycosolation sites of the envelope’s glycoprotein. Further research on PG9 can allow researchers to know the coding sequence on the envelope glycoprotein, or its epitope. By knowing the epitope of the glycoprotein, other antibodies can be engineered to specifically seek out and attach to these binding sites.
It is not all so perfect though unfortunately. Researchers did notice that binding affinity was correlated with the mannose content of the cell. This will certainly lead to more research about the nature of the PG9 and viral envelope glycoprotein interaction. With all said and done, this is a great step in furthering our advances in engineering a plausible vaccine for HIV infection.
1. Jean-Philippe Julien, Jeong Hyun Lee, Albert Cupo, Charles D. Murin, Ronald Derking, Simon Hoffenberg, Michael J. Caulfield, C. Richter King, Andre J. Marozsan, Per Johan Klasse, Rogier W. Sanders, John P. Moore, Ian A. Wilson, and Andrew B. Ward (2013). Asymmetric recognition of the HIV-1 trimer by broadly neutralizing antibody PG9.PNAS 110: 4351-4356Secondary Articles:2. Johnson WE, Desrosiers RC (2002) Viral persistence: HIV’s strategies of immune system evasion. Annu Rev Med :499–518.3. Brower ET, Schön A, Freire E (2010) Naturally occurring variability in the envelope glycoprotein of HIV-1 and development of cell entry inhibitors. Biochemistry 49 :2359–2367.4. Davenport TM, et al. (2011) Binding interactions between soluble HIV envelope glycoproteins and quaternary-structure-specific monoclonal antibodies PG9 and PG16. Journal of Virology 85: 7095–7107.5. Piantadosi A, et al. (2009) Breadth of neutralizing antibody response to human immunodeficiency virus type 1 is affected by factors early in infection but does not influence disease progression. Journal of Virology 83:10269–10274.