VRC01 gp120 complex: Difference between revisions

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. (Wu) 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. (Kwong)  Discovery of the structure of these antibodies can help develop an effective HIV-1 vaccine.

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. (Wu) This conformational change results in the exposure of a binding site for the co-receptor, usually CCR5 OR CXCR4. (Li) 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. (Tran) VRC01 binds to CD4’s binding site on gp120, preventing the CD4 receptor from binding to HIV and infecting the cell. (Wu).

<u>Similarities to other antibodies in complex with gp120</u>. Although only about 50% of the amino acids in the variable region of the heavy chains of different CD4 binding site antibodies were conserved, the structures of each of their complex with gp120 was similar.  Comparison between other CD4 binding site antibodies show that the Arg71 and Asp368 interaction is also conserved.  From sequence analysis of 10 antibodies of the same IGHV1-2*02 germline, 70-90 nucleotide changes are made.  Only two residues changes from this germline mature into the same amino acids. These changes occur in a hydrophobic contact of the heavy chain second complementary-determining region.  The two amino acid changes are Gly56 into Ala56 and Thr57 into Val57. (Wu) More hydrophobic residues at this position led to an increased potency and breadth by increasing contacts with gp120’s bridging domain. (Diskin)  Another conserved interaction is the interaction of Tyr91 and Glu96 of VRC01 with loop D of gp120.  These residues engage loop D by polar interactions. (Scheid)