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.