VRC01 gp120 complex: Difference between revisions

==Introduction==

HIV-1 has a high level of antigenic and genetic diversity.  HIV-1 has also evolved mechanisms to evade the humoral immune response.  These aspects of HIV-1 have made it difficult to develop a vaccine.  After several years of infection, 10 to 25% of HIV-1 infected individuals develop neutralizing antibodies.  Some antibodies target the transmembrane gp41 molecules of the HIV-1 viral spike, however most target the surface protein gp120<ref name="wu">PMID: 21835983</ref>. VRC01 and VRC01-like antibodies bind to gp120 and are able to neutralize about 90% of HIV-1 isolates.  Structural analysis has shown which characteristics of antibodies are essential to its binding with gp120<ref>PMID: 22789610</ref>.  Discovery of the structure of these antibodies can help develop an effective HIV-1 vaccine.

==HIV-1 Neutralization==

HIV-1 enters its host by binding viral gp120, a surface glycoprotein of HIV, to the host cell’s CD4 receptor.  This interaction induces conformational changes in gp120<ref name="wu" />. This conformational change results in the exposure of a binding site for the co-receptor, usually CCR5 OR CXCR4<ref>PMID: 21715490</ref>.  The conformational changes also result in the formation of a pre-hairpin intermediate conformation in which gp41, a transmembrane glycoprotein of HIV, rearranges its molecules so that its N-terminal peptides form a trimer of helices that present a fusion peptide to the target cell.  Once fusion occurs between the fusion peptide and the target cell membrane, HIV is able to enter and infect the target cell<ref>PMID: 22807678</ref>. VRC01 binds to CD4’s binding site on gp120, preventing the CD4 receptor from binding to HIV and infecting the cell<ref name="wu" />.

<StructureSection load='3NGB' color='structure' size='500' frame='true' align='left' caption='VRC01 in complex with gp120' >

==Structural Features==

<u>Similarities to CD4 in complex with gp120</u>. Analysis of VRC01 in complex with gp120 shows that this complex covers 98% of the CD4 binding site.  However, VRC01’s binding site extends outside that of CD4, making it vulnerable to resistance of VRC01 neutralization by antigenic variation. [[Image: Target Site.jpg | thumb | alt=text | Picture 1]] Both the heavy chain and light chain of VRC01 contribute to the contact surfaces of the VRC01 gp120 complex.  The focus of the binding is on the heavy chain second complementary-determining region.  Over 50% of the surface contact involves the heavy chain second complementary-determining region; this is similar to CD4’s interaction with gp120.  Two dominant residues, Phe43 and Arg59, are involved in CD4’s binding to gp120.  Of these two residues, only the arginine interaction is mimicked by VRC01. This dominant interaction is between Asp368 of gp120 and Arg59 of the CD4 receptor and between Asp368 of gp120 and Arg71 of VRC01.  Arg71 and Asp368 form a <scene name='VRC01_gp120_complex/Salt_bridge/1'>salt bridge</scene><ref name="zhou">PMID: 20616231</ref>.   

Also, when 10 best antibody sequences were aligned, it was found that 68 heavy chain residues were conserved and 7 of these residues were involved in the contact between VRC01 and gp120. In comparison only 53 light chain residues were conserved and only 3 of these residues were involved in the contact between VRC01 and gp120.  This is consistent with other research that has shown the light chain of VRC01 having a limited role in attachment to gp120 in comparison to the heavy chain<ref name="scheid" />.  

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