Abstract
The immunodominant epitopes expressed by the HIV-1 envelope protein gp120 are hypermutable, defeating attempts to develop an effective HIV vaccine. Targeting the structurally conserved gp120 determinant that binds host CD4 receptors (CD4BD) and initiates infection is a more promising route to vaccination, but this has proved difficult because of the conformational flexibility of gp120 and immune evasion mechanisms used by the virus. Mimicking the outer CD4BD conformational epitopes is difficult because of their discontinuous nature. The CD4BD region composed of residues 421–433 (CD4BDcore) is a linear epitope, but this region possesses B cell superantigenic character. While superantigen epitopes are vulnerable to a small subset of spontaneously produced neutralizing antibodies present in humans without infection (innate antibodies), their non-covalent binding to B cell receptors (BCRs) does not stimulate an effective adaptive response from B cells. Covalent binding at naturally occurring nucleophilic sites of the BCRs by an electrophilic gp120 (E-gp120) analog is a promising solution. E-gp120 induces the synthesis of neutralizing antibodies the CD4BDcore. The highly energetic covalent reaction is hypothesized to convert the abortive superantigens–BCR interaction into a stimulatory signal, and the binding of a spatially distinct epitope at the traditional combining site of the BCRs may furnish a second stimulatory signal. Flexible synthetic peptides can detect pre-existing CD4BDcore-specific neutralizing antibodies. However, induced-fit conformational transitions of the peptides dictated by the antibody combining site structure may induce the synthesis of non-neutralizing antibodies. Successful vaccine targeting of the CD4BD will require a sufficiently rigid immunogen that mimics the native epitope conformation and bypasses B cell checkpoints restricting synthesis of the neutralizing antibodies.
Highlights
In 2008, an estimated 33.4 million people worldwide were living with HIV/AIDS; 2.7 million people were newly infected; and 2.0 million people died due to AIDS
This provides a selective pressure for structural conservation of the gp120 determinant that binds CD4, and the CD4BD has remained mostly conserved while the sequence of other gp120 regions has increasingly diverged as various Group M HIV-1 strains have evolved over the course of the pandemic in the last 3 decades
We reported CD4BDcore-specific antibodies with potent neutralizing activity directed to genetically heterologous HIV strains in the blood of three hemophilia A patients who survived infection for over two decades with little or no requirement for Anti-retroviral therapy (ART) (Planque et al, 2010)
Summary
In 2008, an estimated 33.4 million people worldwide were living with HIV/AIDS; 2.7 million people were newly infected; and 2.0 million people died due to AIDS. Many recent vaccine development efforts have been focused at the envelope determinants essential for interaction with host receptors Such viral determinants are likely to be structurally conserved to maintain the ability to the virus to infect cells. Initial HIV binding to host cell CD4 receptors is an obligatory step for infection by all HIV-1 subtypes This provides a selective pressure for structural conservation of the gp120 determinant that binds CD4 (the CD4 binding determinant, CD4BD), and the CD4BD has remained mostly conserved while the sequence of other gp120 regions has increasingly diverged as various Group M HIV-1 strains have evolved over the course of the pandemic in the last 3 decades. Antibodies may facilitate removal of virus-infected cells by natural killer cells This mechanism is designated antibody-dependent cell-mediated viral inhibition, involving recognition of an HIV epitope by the antibody variable domains, followed by binding of the antibody constant domain region to Fc receptors expressed by natural killer cells (Bialuk et al, 2011).
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